Imaging technique findings in the right-sided infective endocarditis.
\r\n\t
\r\n\tGenetic predisposition is converted into a pathological phenotype only under the effect of environmental factors.
\r\n\tMultifactorial disorders are considered to be the most common features that affect people, such as diabetes, high blood pressure, coronary heart disease, and cancer, as well as some of the common isolated birth defects, including cleft lip or palate, neural tube defects, congenital heart disease, and clubfoot.
\r\n\t
\r\n\tMultifactorial inheritance did not follow a simple Mendelian pattern. However, the recurrence risk of multifactorial disorders is higher in relatives of affected individuals than in the general population. The empirical risks of a multifactorial disorder are based on large population studies.
\r\n\t
\r\n\tIt is important to understand the multifactorial transmission model for proper genetic counseling and for avoiding environmental factors, a measure that could ensure the prophylaxis of these common diseases.
\r\n\tThis book intends to provide valuable evidence-based information, a comprehensive overview of this complex pathology. The aim will be to highlight the importance of collaboration and multidisciplinary teams for multifactorial disease management in an easy-to-follow format.
Infective endocarditis (IE) at the right side of the heart is quite rare; it represents the 5–10% of IE cases. It is seen most frequently in people with intravenous drug addiction; nevertheless, other portions of the population are in high risk of developing this disease such as patients with indwelling catheters, cardiac devices, congenital cardiac pathologies, and immunocompromised diseases [1, 2, 3].
The evolution of right-heart IE is much better than the left-side IE with a lower rate of mortality (3–30%) [3]. This pathology is more frequent in people between 20 and 61 years, with a mean age of 38 ± 15 years [4].
Staphylococcus aureus is the predominant organism (60–90% of cases) with the methicillin-resistant strains becoming more prevalent lately [3, 5]. The tricuspid valve is by far the most effective structure (90%) in right-side infective endocarditis (RSIE) [5].
Common symptoms secondary to right-sided endocarditis are the respiratory symptoms characterized by a cough, hemoptysis, persistent fever, dyspnea, and chest pain [4].
In exceptional circumstances, right-heart failure can arise, generated by the increase in pulmonary pressure, severe tricuspid valve regurgitation, or obstruction of pulmonary circulation through multiple pulmonary emboli [4, 6].
The diagnosis of RSIE is often delayed because the signs and symptoms are relatively different concerning the LSIE clinical setting; the Duke’s modified criteria do not have value in the RSIE. The low incidence of RSIE also plays an essential factor in the underdiagnosis of this disease.
There are reports in which the 76% of the patients had gotten an antibacterial treatment before the endocarditis’s diagnosis because they developed some signs and symptoms that were misunderstood as a febrile syndrome or pneumonia [4].
An acute beginning of the disease is seen at the majority of the patients; only a few cases have been reported with chronic symptoms (more of 2 months) [4].
It is frequent that right-side vegetations dislodge microemboli to the pulmonary region. The pulmonary embolism (PE) can induce pulmonary infarction, abscesses, pneumothoraxes, and purulent pulmonary effusions.
Persistent fever associated with pulmonary events, anemia, and microscopic hematuria, the so-called “tricuspid syndrome,” is the sign of clinical alert for tricuspid valve IE [3, 4, 7].
Revilla et al. found 24% of their patients with this syndrome, and the other 65% had at least two of the three signs [4].
Nowadays it is routinary to order blood tests for any patient admitted at the hospital, and it is reasonably used if the suspicion of infection is thought. Some findings such as high titers of white blood cells, procalcitonin, and C-reactive protein can support the infection diagnosis; nevertheless, these variables are not used as criteria to diagnose infective endocarditis [5, 8].
The anemia has been described as part of the tricuspid syndrome, so the values of hemoglobin and hematocrit below the normal range can be found in the blood test, which probably will reveal a normocytic, normochromic anemia patron [3, 4, 7].
The urine test can show microhematuria which also is part of the tricuspid syndrome.
Right-sided endocarditis in IVDA is commonly caused by S. aureus and Pseudomonas aeruginosa, and other Gram-negative organisms, fungi, streptococci, and enterococci have also been found [4, 6].
In the majority of patients, the microorganism can be identified through blood cultures if they are adequately collected. The 2015 ESC endocarditis guidelines recommend a technique of recollection minutely sterile of at least three sets of samples with an interval of 30 minutes; each sample must contain 10 ml of blood and should be incubated in both aerobic and anaerobic atmospheres. Another crucial aspect is the recollection of samples from a peripheral vein instead of central venous catheter due to the risk of contamination and wrong interpretation [5].
Occasionally, the blood cultures can be negative by different reasons, especially if an antimicrobial therapy was established before the acquisition of the samples. The blood cultures usually become negatives after 48 hours from the beginning of antibiotics [4].
Currently, the diagnosis of IE requires the finding of an infective process inside the heart, reason why the imaging techniques are valuable to diagnose or discard IE. The echocardiography is the most important and more used tool to diagnose, manage, and monitor patients with IE [5].
However, other imaging methods have been developed in the last decades, allowing us to back the diagnosis of IE when the echography is not entirely clear in some cases (Table 1).
Imaging technique findings in the right-sided infective endocarditis.
It can be quite normal or shows a variety of findings, such as cardiomegaly, pulmonary septic emboli, or pleural effusion [4].
The benefits that the echocardiography brought to the cardiology area are well-known, and they can help us to detect anomalies related to IE. It is the gold standard imaging test for IE, becoming one of the first steps that we must do if IE is suspected [3, 9].
The same as the LSIE, the transthoracic echocardiography (TTE) is the first modality recommended to perform if RSIE is suspected. The sensitivity of TTE to detect vegetations is roughly 75% and its specificity over 90%. When the hunch of IE is high, but the TTE is negative, the transesophageal echocardiography (TOE) must be used because its sensitivity is higher than TTE, approximately 96%. Some experts indeed recommend TOE even if the TTE is positive for IE; nevertheless, it does not apply for RSIE in which an explicit finding of IE is enough for the diagnosis [5, 9].
The 2015 ESC guidelines also suggest the use of TOE when the suspicion of IE is present in patients with a prosthetic heart valve and intracardiac device [5].
There are some “typical lesions” of IE that we can detect in the echocardiography, such as vegetations, abscess, pseudoaneurysm, valve aneurysm, perforation, fistula, and dehiscence of the prosthetic valve, being the vegetation of the landmark lesion of this disease (Figure 1) [5, 9].
Transesophageal echocardiogram: a hyperechoic lesion (red arrow) is seen at level of pulmonary valve, prolapsing to right ventricle outflow tract.
Occasionally, parts of the vegetations can be visualized floating in the right ventricle or entrapped in the subvalvular apparatus. TTE usually allows assessment of tricuspid valve involvement because of the valve’s anterior location and large natural vegetations. TOE imaging is more sensitive to detect vegetations than TTE imaging, especially in the case of abscesses, and associated left-sided involvement [6].
Cardiac computed tomography (CCT) can improve the diagnosis of IE when abscesses and pseudoaneurysm are present, due to its higher sensitivity (approximately 81%) in comparison with TTE and TOE (roughly 63%). The combination of echocardiography and CCT to diagnose abscess/pseudoaneurysm reaches 100% sensitivity. In pulmonary/right-sided endocarditis, CT may reveal concomitant pulmonary disease, including abscesses and infarcts [5, 10].
The use of MR in the IE setting is focused on the diagnosis of cerebrovascular events related to IE. This imaging modality has better sensitivity than CT to detect brain hemorrhage and infectious intracranial aneurysms (IIAs) [5, 11].
The incorporation of positron-emission tomography (PET) in the modified Duke’s criteria is addressed to enhance the IE diagnosis in some situations where the clinical suspicion is not always confirmed with the echocardiography. This imaging technique is especially valuable in the diagnosis of prosthetic valve infective endocarditis (PVIE) [5, 12].
There are also reports where the PET helped to determine the extension of pacemaker or defibrillator infection, consequently improving the adequate surgical intervention [13].
Peripheral embolic and metastatic infectious events can also be detected with this technique; nevertheless, their specificity is lower in brain septic emboli [5].
A correct interpretation of PET must be taken in some conditions which can make us misinterpret the findings, for instance, a recent cardiac surgery usually shows enhancement at the mediastinal area due to the inflammatory response. Some conditions can show similar patterns to that of IE, such as an active thrombus, soft atherosclerotic plaques, vasculitis, primary cardiac tumors, cardiac metastasis from a non-cardiac tumor, postsurgical inflammation, and foreign body reactions [5].
The same fundamental aspects about the antibiotic therapy in IE is applied to the right-sided endocarditis, making emphasis in the early and proper setting of the cultures, the prompt and adequate starting of empirical antimicrobial therapy (if the suspicious of IE is higher), and the administration of a culture-antibiogram sensible antibiotic.
One aspect that changed in the antimicrobial treatment of RSIE in comparison with LSIE is the duration of the therapy when the implicated bacteria is the methicillin-sensible Staphylococcus aureus, due to the 2015 European Society of Cardiology guidelines for the management of infective endocarditis recommending a short treatment of 2 weeks in this scenario. This approach is attributed to the less aggressive evolution of RSIE with these bacteria [5].
The prophylactic treatment in the patient with high suspicion of RSIE should cover Staphylococcus aureus, streptococci, and enterococci and should include penicillinase-resistant penicillins or vancomycin, depending on the local prevalence of methicillin-resistant Staphylococcus aureus (MRSA) [6].
In RSIE, the medical treatment usually resolves the disease; nevertheless, the surgery for right-sided infective endocarditis is recommended in the following situations: (1) right-heart failure due to severe tricuspid valve regurgitation, (2) inability to eliminate bacteremia or organisms resistant to culture-directed antibiotic treatment, within 7 days, and (3) tricuspid valve vegetations >20 mm [1, 2, 3, 5].
During the surgery, most of the infected tissue must be removed; if it is possible, we should try to repair the native valve but guarantee the adequate functioning of the valve. When a valve-sparing is impossible, the implantation of a prosthetic valve is necessary, always trying to use the less foreign material to diminish the risk of IE recurrence [14].
Sometimes the endocardial destruction is highly extensive that compromises the valve repairing as well as the valve prosthesis replacement; this scenario is hideous and requires the reconstruction of the annular structure using endocardium patch or other materials.
Another potential complication of IE can be the formation of ventricular septal defect due to the infection’s aggressiveness which can show communication between the right ventricle and left ventricle through the membranous septum. This anatomical defect also can be figured out with a pericardium patch [15].
Some surgeons can feel uncomfortable with the idea of setting up a prosthetic valve in tricuspid position due to being afraid of high gradients through the valve and the potential thrombosis of the prosthesis. However, large prostheses (>30 mm) guarantee low transvalvular gradients, and the incidence of thrombosis is small if the patient has an adequate anticoagulation control (biological and mechanic prostheses are anticoagulated). Moreover, bioprosthesis degeneration develops more slowly owing to the low-pressure conditions in the right ventricle [6].
In 1991, Arbulu et al. published a paper showing their experience in tricuspid valvulectomy without replacement, generally indicated for IVDA, to avoid the potential IE recurrence; nevertheless, about 25% of patients cannot tolerate tricuspid regurgitation and require a second operation for tricuspid valve replacement [14, 16].
RSIE implies a better prognosis than LSIE; the previous study revealed the mortality of right-sided IE is 12% in-hospital patients and 0–7.3% for surgical patients. However, these percentages increase at least twice in patients with intensive care unit (ICU) admission; actually, this issue will be described forward [3, 9].
Concomitant left-sided IE carries a worse prognosis than right-sided infection alone, due predominantly to its greater likelihood for invasion and abscess formation [7].
The high increase of bacterial resistance throughout the last decades has produced a change in the IE guidelines from 2002. The same criteria for LSIE are applied to RSIE regarding the antimicrobial prophylaxis, being reserved only in patients with a high risk of endocarditis, particularly those with PVIE [5].
Nevertheless, there are some aspects that the last IE guidelines do not approach which are very relevant that need to be highlighted. One of the most critical issues is the quite strict aseptic measurements that healthcare professionals must take during routine procedures, especially invasive maneuvers in high-risk patients such as immunocompromised, hemodialytic (HD), cyanotic congenital heart disease (CHD) patients, etc.
The change in some hospital policies can diminish the incidence of bacteremia and IE, such as have been shown in some publications [17].
There are few publications about the characteristics of RSIE in ICU. It is noteworthy that patients with IE admitted in ICU have a higher rate of morbidity and mortality than non-ICU patients. The only study describing the outcome of IDUs with RSIE needing ICU admission reported a mortality of 26% [2].
Some factors have been associated with a worse prognosis: acute respiratory failure requiring mechanical ventilation, shock, Simplified Acute Physiology Score (SAPS II) ≥ 20, and Sequential Organ Failure Assessment (SOFA) ≥ 3 [2, 5].
Other elements that play an essential role at the 30-day survival are age <45 years, Charlson score < 3, endocarditis diagnosed before ICU admission, aminoglycoside use, the presence of septic pulmonary embolism, and a single surgical indication for patients needing a surgical procedure [2].
Reasons for admission to the ICU were a congestive cardiac failure (64%), septic shock (21%), neurological deterioration (15%), and cardiopulmonary resuscitation (9%). Younger patients have a better prognosis because they usually present a minimal dysfunction of the right-sided valve, low risk of pulmonary embolism, and reasonable response to appropriate antibiotic therapy [2].
Opposite to the last IE guidelines, which no longer recommend the aminoglycosides in the treatment of native valve staphylococcal endocarditis, Georges et al. found a better survival in their patients treated with a combination of penicillins or vancomycin with gentamicin [2].
It is imperative to describe this pathology in the people with susceptible risk factors (Table 2).
Characteristics of principal risk factors in the right-sided infective endocarditis.
AVF: arteriovenous fistula, HD: hemodialytic, HIV: human immunodeficiency virus, IE: infective endocarditis, RSIE: right-sided infected endocarditis, VSD: ventricular septal defect.
The majority of cases of RSIE reports in the literature are in drug abusers. This kind of populations of RSIE represents the 32–86% of all IE [2, 3].
There are multiple explanations about the preference of infection in the right side of the heart at this group of the population, being the leading causes of the poor hygiene with unsafe injection practices and the affected immunology well-being. The higher bacterial load and the variety of effects of injected substances over the endocardium also play an essential role in the physiopathology of the infection [7].
The incidence of reinfections and reoperations is about 28 and 20%, respectively; however, the survival described in some papers is almost equal between drug abusers and not drug abusers, in which results are very striking [7].
Sometimes IVDA also presents human immunodeficiency virus (HIV) which can aggravate the predisposition to IE if this disease is not well-controlled. The death rates in this subgroup of patients are about 5–10% [1]. The HIV affects both humoral and cellular immunities which provoked a predisposition for recurrent episodes of bacteremia that cause valve damage, fibrin deposition, thrombus formation, and adherence by bacteria in the endocardium; it is common to find abscess developments and large vegetations, which are indications for early surgical treatment [18].
The choice of empiric antimicrobial therapy depends on the suspected microorganism and type of drug and solvent used by the addict and the location of infection.
As previously was described, the empirical antimicrobial therapy must cover S. aureus; the combination of penicillinase-resistant penicillins or vancomycin or daptomycin with gentamicin is recommended [5].
The 2015 ESC IE guidelines recommend an antipseudomonal therapy in patients with pentazocine addiction if IE is suspected; nevertheless, there are few and relatively old studies about this issue [5, 19, 20].
If an IVDA uses brown heroin dissolved in lemon juice, Candida spp. (not Candida albicans) should be considered and antifungal treatment added [5].
Although the majority of IE at the right side of the heart is fairly reported in IVDA, there is an increasing incidence in another type of patients, mainly highlighting the people with indwelling catheters and cardiac devices. The 5–10% of RSIE occur in nonaddicted patients [3].
It is estimated that more than 3 million people worldwide require dialysis for end-stage renal disease, and this number is expected to rise sharply because of the aging of the population and an increasing prevalence of diabetes and cardiovascular comorbidities paralleled by a decline in cardiovascular mortality, particularly in very elderly patients (>80 years). For instance, in the United States, this augmentation is about 3.2% per year [21, 22].
Hemodialysis patients are at increased risk for bacteremia, including an estimated 37,000 central line-associated bloodstream infections related to outpatient hemodialysis in the United States in 2008. The elevated incidence of bacteremia increases the risk for infective endocarditis [22, 23].
The average duration on HD before the diagnosis of IE was 30 months (range, 4–66 months). IE is one of the most important causes of increased mortality and morbidity among hemodialysis patients [24].
The European Heart Journal states that more than two-thirds of patients undergoing hemodialysis suffer from some infection and that one-third of these patients experience IE [24].
IE occurs 18 times more frequently in chronic HD patients than in the general population [25, 26].
The use of temporal or permanent central catheters, the constant puncture of arteriovenous fistulas, the long and frequent hospitalizations that some of these patients have to suffer during their disease, the various surgical procedures related with the creation of fistulas, and the underlying alteration of their defenses become susceptible to this population to develop IE.
The IE in HD patients is calculated about at 8% of all observed IE cases regarding the largest international cohort collected to date [27].
The incidence of IE usually increases with the time after the initiation of hemodialysis; however, some studies found a rise of this incidence in the first 5 months after the initiation of hemodialysis [26, 28]. This contradictory results can be probably due to the aseptic technique during the manipulation of the catheter and arteriovenous fistulas of these patients.
Patients in HD also present an increase in the incidence of endocarditis after aortic valve replacement surgery, affecting at the same time the short-term and long-term survival [22].
Most of the studies show that central catheters are a risk factor for bacteremia and endocarditis [6, 7, 10]; nevertheless, Farrington et al. did not find an increase of endocarditis in patients with central catheters in comparison with patients with arteriovenous fistulas [22].
Besides, the rates of IE are more significant in patients with non-cuffed catheters than cuffed catheters; the vascular grafts have more incidence of IE than AV fistulas. Furthermore, peritoneal dialysis has then lesser rates of IE due to the lack of contact of the line with luminal vessels [29].
The morbidity and mortality are higher than the general population; in the 20% of hemodialysis-related IE, the tricuspid valve is the principal place affected at the right side of the heart.
The pathogenesis of IE in HD patient can be attributed to recurrent episodes of bacteremia, the immunological compromise of hemodialytic patients and heart valvular deterioration-calcification frequently founded in this patients.
It can sound logical that the majority of cases of IE in HD patients should happen on the right cavities, similar to what occurs in IVDA; however, the left-side heart (90%) is the more frequent infected place in HD patients, the mitral being the main valve affected. The affectation of the right cavities is roughly 10%. Nevertheless, some papers report an incidence of RSIE in HD patients of between 0 and 50% [30, 31].
Between the multiple explanations of pathogenesis RSIE in HD patients, the high turbulent flow throughout the valves can provoke a deterioration at these structures, becoming more susceptible to bacterial implantation. Nonetheless, the low pressures at the right cavities might not present the same effect in their valves. One possible cause can be the associated pulmonary hypertension that some patients express, due to multiple factors, such as an increased cardiac output (hypervolemic condition and arteriovenous fistula), an increased pulmonary vascular resistance (uremic endothelial dysfunction and pulmonary artery calcifications), and elevated pulmonary capillary wedge pressure caused by heart failure or mitral valve disease [17].
Patients in HD have an increased risk of developing IE due to all the reasons described before, so to take some measurements sounds logical to diminish the incidence of bacteremia which can result in an IE.
In some hospitals, their politics have been changed regarding the hemodialysis procedure with the intention to ameliorate the arteriovenous life expectancy and decrease the local and systemic infections. For instance, Oun HA et al. have published a lowering in the bacteremia and IE at his hospital adopting new strategies, such as changing the lock solution to taurolidine, cleaning the puncture site with chlorhexidine 2%, and using the buttonhole technique instead of the rope ladder technique. Nonetheless, it is important to mention that the buttonhole technique had a modest but not significative rising of bacteremia following the move to buttonhole [26].
The arteriovenous fistula (AVF) must always be the best option to perform HD due to their low rates of bacteremia and IE, so, it is imperative to develop an adequate surgical technique and improve the care of the fistula. Whenever it is possible, the fistula must be carried out at the distal part of the arms, trying to preserve the proximal areas to future AVF if the distal fistula fails at some point. If the HD needs a temporary or permanent catheter, the cuffed ones always are preferable to non-cuffed catheters, because the former cause fewer rates of IE [29].
The patient and healthcare personnel must be informed and trained regarding the proper care of the AVF and catheters to lower the probability of bacteremia and IE. The cleaning of the surgical area is paramount as well as the correct AVF puncture.
Nowadays ICD are widely used worldwide; their implementation in the cardiology area has improved the quality of life of many people and increased the survival; nonetheless, they have side defects, the endocarditis being one of the most severe complications.
The IE on a cardiac device is increased in the last 10 years in the first-world countries, even becoming the most common cause of IE in some regions. This phenomenon is caused mainly by the rise in the longevity in these countries which results in a growing number of intracardiac devices implanted (pacemakers, cardiac defibrillator, cardiac resynchronizer, or ventricle assist device) [32].
This IE is associated with a worse prognosis and high mortality (11–36%) [32, 33, 34]. The pacemaker generator or lead change is the higher factor of risk for IE on the cardiac device. The tricuspid valve is the most common site of RSIE associated with this kind of devices [7, 35].
The removal of the infected device is mandatory in the treatment of intracardiac device infective endocarditis (ICDIE) because it decreases the hospital mortality [32]. Patients with device-related infection and intracardiac vegetations higher or equal at 1 cm have historically undergone surgery for device removal due to the potential risk for septic embolization [34].
The risk of IE in patients with adult congenital heart disease (ACHD) is substantially higher (15–140 times) than in the general population. The RSIE in CHD is more often in adults than pediatric patients [5, 36].
The ventricular septal defect (VSD) is the most frequent anomaly in right-sided IE with an incidence of 0.2–2% of all IE [37].
The risk of IE can occur either in repaired or not repaired VSD, with a higher increase in the last one [38].
A recent paper from Tutarel et al. found an incidence of 15.9% of IE in patients with VSD; the 50% of these cases were associated with infections of either the tricuspid valve or the right ventricular outflow tract [36].
The 2015 ESC IE guidelines describe that the distribution of causative organisms does not differ from the pattern found in acquired heart disease, with streptococci and staphylococci being the most common strains. Another study found the streptococci responsible for 50% of congenital heart disease infective endocarditis (CHDIE) and the staphylococci with a 31% incidence [5, 36].
The pulmonary valve is affected in almost 32% of patients from which over an 84% are prosthetic and near 16% native valve [36].
Unlike the left-sided IE mainly occurring on the aorta or mitral valve, right-sided IE could involve the tricuspid valve (82%), pulmonary valve, eustachian valve, interventricular septum, right ventricular free wall, or CS [4, 9].
The vast majority of RSIE cases involve the TV (approximately 90%). The high risk of vegetations on the TV is septic PE resulting in various pulmonary complications such as pneumonia and pulmonary abscess.
Uncomplicated tricuspid valve endocarditis can be successfully treated medically in 80% of patients and in the remaining 20% with very large vegetations and expectably poor antibiotic penetration [6].
The infection of the native tricuspid valve in nonaddicted adults occurs in younger patients (under 50 years). In the majority of cases (70%), there are underlying medical conditions such as alcoholism, abortion, colon disease, immunodeficiency, permanent catheters, septic processes in the oral cavity, skin, or genitals, etc. The 25% of cases require valve replacement or surgery [3] (Figure 2).
Pulmonary native endocarditis: a giant mass anchored to the posterior leaflet of pulmonary valve [42].
RSIE in PV happens in less than 10% of the patients [7]. Most of the cases of pulmonary valve infective endocarditis (PVIE) are provoked by prosthetic material present at this place due to previous surgeries or interventional procedures focused on figuring a congenital disease out.
Bovine jugular grafts are associated with a significantly higher risk of late endocarditis compared with homografts [39].
However, Robichaud et al. did not find an increased risk of PVIE regarding the type of valve, including bovine jugular vein grafts [40].
The rate of IE in transcatheter pulmonary valve implantation is higher than surgical homograft implantation [41].
Uniquely few case reports have been published about RSIE in other locations different to tricuspid and pulmonary valves.
Reports of eustachian valve infective endocarditis (EVIE) are approximately 29 cases [43]. An incidence of 3.3% in patients with right-sided endocarditis has been reported [44].
Eustachian valve is a rudimentary structure in adults and, during fetal life, directs oxygenated blood from the inferior vena cava through the foramen ovale and into the left atrium [43, 45].
IVDA is the main high-risk population to develop an EVIE (over 50% of cases). Staphylococcus aureus is the most common bacteria implicated in this process [43]. TOE is necessary to identify the vegetation at eustachian valve because this structure is not accessible with TTE [45].
There are only eight reported cases of IE in the coronary sinus (CS). The clinical manifestations, the complementary test, the responsible bacteria, and antibiotic treatment are very similar to the other RSIE locations. The CSIE has some features; the CS is always dilated and generally the only affected valve; the vegetation is usually mobile and has a tubule shape with a length of >10 mm [9, 46].
RSIE is a pathology scarcely studied because there are few articles released about it. One of the significant reasons about the RSIE little information is the low incidence of this disease; nevertheless, the rates of frequency of this infection are rising nowadays due to the steady increase of HD patients and implanted ICD.
RSIE clinic criteria are necessary to establish to help in the diagnosis of the disease, such as modified Duke criteria.
Healthcare personnel must be aware of this illness, keeping their suspicion in high-risk patients and performing the proper complementary test to confirm or discard this infection.
Hospital policies should be continuously updated to diminish the incidence of RSIE, an adequate epidemiologic analysis about RSIE cases, the population in potential risk to acquire the infection, and the most frequent bugs implicated in this one.
None.
ACHD | adult congenital heart disease |
AVF | arteriovenous fistula |
CHD | congenital heart disease |
CHDIE | congenital heart disease infective endocarditis |
CS | coronary sinus |
CT | computed tomography |
EVIE | eustachian valve infective endocarditis |
HD | hemodialytic |
HIV | human immunodeficiency virus |
ICD | intracardiac devices |
ICU | intensive care unit |
IE | infective endocarditis |
IIAs | infectious intracranial aneurysms |
IVDA | intravenous drugs addiction |
LSIE | left-side infective endocarditis |
MRSA | methicillin-resistant Staphylococcus aureus |
MR | magnetic resonance |
PET | positron-emission tomography |
PE | pulmonary embolism |
PVIE | prosthetic valve infective endocarditis |
PV | pulmonary valve |
RSIE | right-side infective endocarditis |
SAPS | Simplified Acute Physiology Score |
SOFA | sequential organ failure assessment |
TTE | transthoracic echocardiography |
TOE | transesophageal echocardiography |
TV | tricuspid valve |
VSD | ventricle septal defect |
DNA information is stored in the form of a code that constitutes four chemical bases namely: cytosine (C), adenine (A), thymine (T), and, lastly, guanine (G). The human DNA has approximately 3 billion bases, and not <99% of these bases are similar in all individuals. The sequence of these bases governs the available information for maintaining and building an organism, similar to the manner in which alphabetical letters are arranged to form sentences and words [1].
The chemical bases in a DNA pair up (C with G and A with T), in order to produce units known as base pairs. In addition, each base is attached to a phosphate molecule and a sugar molecule. Together, a phosphate, sugar, and base are referred to as a nucleotide. The nucleotides are organized in two long strands thereby forming a spiral known as a double helix. A double helix’s structure resembles a ladder, with the phosphate and sugar molecules forming the ladder’s vertical sidepieces. On the other hand, the base pairs form the rungs of the ladder.
Many anticancer drugs in clinical use interact with DNA through intercalation, which can be defined as the process by which compounds containing planar aromatic or heteroaromatic ring systems are inserted between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall stacking pattern due to Watson-Crick hydrogen bonding [2, 3].
DNA consists of two complementary anti-parallel sugar phosphate poly-deoxyribonucleotide strands that are associated with specific hydrogen bonding between nucleotide bases. The two strands are held together primarily through Watson-Crick hydrogen bonds where A forms two hydrogen bonds with T and C forms three hydrogen bonds with G (Figure 1). The structure of these paired strands defines the helical grooves, within which the edges of the heterocyclic bases are exposed. The biologically relevant B-form of the DNA double helix is characterized by a shallow-wide major groove and a deep-narrow minor groove. The chemical structure (feature) of the molecular surfaces in a given DNA sequence is well known in either groove. This forms the basis for molecular recognition of duplex DNA by small molecules and proteins [4, 5].
Watson-Crick pairing between purine and pyrimidine bases in complementary DNA strand.
DNA as carrier of genetic information is a major target for anticancer drug interaction because of the ability to interfere with transcription and DNA replication, a major step in cell growth and division. There are three principally different ways of anticancer drug binding. First is through control of transcription factors and polymerases. Here, the anticancer drugs interact with the proteins that bind directly to DNA. Second is through RNA binding to DNA double helices to form nucleic acid triple helical structures or RNA hybridization to exposed DNA single strand regions that will be forming DNA-RNA hybrids and it may interfere with transcriptional activity. Third is through small aromatic ligand molecules that bind to DNA double helical structures through non-covalent interaction either by intercalating binder or by minor groove binders (Figure 2) [6, 7]. Therefore, intercalation can be defined as the process by which compounds containing planar aromatic or heteroaromatic ring systems are inserted between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall stacking pattern due to Watson-Crick hydrogen bonding [8]. In addition, intercalation binding involves the insertion of a planar molecule between DNA base pairs, which results in a decrease in the DNA helical twist and lengthening of the DNA. While groove binding, unlike intercalation, does not induce large conformational changes in DNA and may be considered similar to standard lock-and-key models for ligand-macromolecular binding. In addition, Groove binders are usually crescent-shaped molecules that bind to the minor groove of DNA [7].
Groove binding to the minor groove of DNA (left) and the intercalation into DNA (right).
In order to accommodate the binder (like intercalation binder), DNA must undergo a conformational change to create a cavity for the incoming chromophore. The double helix is therefore partially unwound, which leads to distortions of the sugar-phosphate backbone and changes in the twist angle between successive base pairs (Figure 3) [8]. Once the drug has been sandwiched between the DNA base pairs, several non-covalent interactions such as Van der Waals interaction and hydrogen bonding optimizes the stability of the complex.
Deformation of DNA by an intercalating agent.
The study of interaction between drug molecules and DNA is very exciting and significant not only in understanding the mechanism of interaction, but also for the design of new drugs. However, the mechanism of interactions between them is still relatively little known. By understanding the mechanism of interaction between them, designing of new DNA-targeted drugs and the screening of these in vitro will be possible [9]. Many of the most valuable anticancer drugs currently used in therapy interact with DNA either by a covalent or non-covalent mechanism. Unfortunately, several of them show a considerable toxicity when the DNA molecular target is present in both normal and tumor cells [10]. The covalent type of binding of drug-DNA is irreversible and invariably causes the complete inhibition of DNA processes and subsequent cell death. A major advantage of covalent binders is the high binding strength. However, covalent bulky adducts can cause DNA backbone distortion, which affect both transcription and replication (disrupting protein complex recruitment). The covalent binders are also called alkylating agents due to adduct formation because they are used in cancer treatment to attach an alkyl group (CnH2n+1) to DNA [11]. Table 1 lists the different types of drug-DNA interactions with suitable examples. In addition, some important examples of a cross-linking agent covalent and non-covalent binder were shown in Figure 4 [5, 12].
No. | Type of interaction | Example |
---|---|---|
1 | Covalent bonding | Nitrogen mustard, carboplatin and cyclophosphamide |
2 | Non-covalent bonding | Ethidium bromide and quinacrine |
Listing the different types of drug-DNA interactions with suitable examples.
Chemical structure of some covalent and non-covalent binders of DNA.
Non-covalent DNA interacting agents (groove, intercalators, and external binders) are generally considered less cytotoxic than agents producing covalent DNA adducts and other DNA damage. The non-covalent binding type is reversible and is typically preferred over covalent adduct formation keeping the drug metabolism and toxic side effects in mind. In addition, non-covalent DNA interacting agents can changes DNA conformation, DNA torsional tension, interrupt protein-DNA interaction, and potentially lead to DNA strand breaks [11].
Hairpin minor grove binding molecules have been identified and synthesized that bind to G-C reach nucleotide sequences. Hairpin polyamides are linked systems that exploit a set of simple recognition rules for DNA base pairs through specific orientation of imidazole (Im) and pyrrole (Py) rings (Figure 5) [13]. They originated from the discovery of the three-ring Im-Py-Py molecule that bound to minor groove DNA as an antiparallel side by side dimer.
Structure of hairpin polyamide Im-Py-Py.
The solid phase synthesis of polyamides of variable length has produced efficient ligands. The advantage of polyamide ligand design has been reached with finding structures able to recognize DNA sequences of specific genes. Moreover, a new strategy of rational drug design exploits the combination of polyamides with bis-intercalating structures. The new synthetic compound showed a resistant against multidrug resistance in which small aromatic compounds are efficiently expelled from the cell-by-cell membrane transport proteins that commonly referred to as ABC transporters or ATP binding cassette proteins [14].
When a compound intercalates into nucleic acids, there are changes, which occur in both the DNA and the compound during complex formation that can be used to study the ligand DNA interaction. The binding is of course an equilibrium process because no covalent bond formation is involved. The binding constant can be determined by measuring the free and DNA bound form of the ligand. In addition, DNA double helix structures are found to be more stable with intercalating agents present and show a reduced heat denaturation. Correlating these biophysical parameters with cytotoxicity is used to support the antitumor activity of these drugs as based on their ability to intercalate in DNA double helical structures. [15].
Improvement of anticancer drugs based on intercalating activity is not only focused on DNA-ligand interaction, but also on tissue distribution and toxic side effects on the heart (cardiac toxicity) due to redox reduction of the aromatic rings and subsequent free radical formation. Free radical species are thought to induce destructive cellular events such as enzyme inactivation, DNA strand cleavage and membrane lipid peroxidation [16, 17].
Cisplatin (cis-[PtCl2(NH3)2]) is the most widely used anticancer drug today. Since the development of cisplatin became one of the main biological targets for the antitumor compounds. It is used against ovarian, cervical, head and neck, esophageal and non-small cell lung cancer. However, chemotherapy treatment by cisplatin comes with a price of severe side effects including nausea, vomiting and ear damage, as cisplatin not only attacks cancer cells, but also healthy cells. It is therefore important to elucidate the details of the cisplatin mode of action to design new cisplatin analogs that specifically target cancer cells. Furthermore, most cancer cells are insensitive towards cisplatin or develop resistance. There is therefore, also a need for cisplatin analogues with a broader range of cytotoxicity. The search for new analogues and the elucidation of the complete mode of action have been going on for more than 40 years and there is an enormous amount of data available for researchers. Still, the picture of how cisplatin works is incomplete [11, 18].
Cellular DNA has been shown to be the primary target for cisplatin, although cisplatin can react with several other cellular components. In the cell, the salt concentration is significantly lower (~20 mM) and cis-[PtCl2(NH3)2] is hydrolyzed by high salt concentration (>100 mM) to the probable active species cis-[PtCl(OH2)(NH3)2]+. The hydrolyzed product binds to DNA and preferentially to guanine N7> > adenine N7 > cytosine N3, first as a monoadduct, then forming a bidentate adduct. The primary products are 1,2-intrastrand cross-links of GpG (60–65%) or ApG (20–25%) sequences. A smaller amount corresponds to 1,3-intrastrand or G N7–G N7 interstrand adducts. The most common binding sites on the nucleobases for Pt are shown in Figure 6 [18]. The big arrow on guanine indicates the overall favorable coordination site in DNA, the arrow towards thymine is dotted because the proton has to be removed before Pt association.
The structure of the most common binding sites on the nucleobases for Pt. The big arrow on guanine indicates the overall favorable coordination site in DNA, the arrow towards thymine is dotted because the proton has to be removed before Pt association.
The formation of these 1,2-intrastrand cross-links alters the duplex conformation. The most dramatic effect is unwinding of the two strands and bending of the DNA double helix (several values for the bend angle are reported in the range 20–80°). The platinated adducts are assumed to be recognized by proteins, followed either by stabilization of the distorted DNA structure or removal of the lesion through repair [18]. The deformation of the DNA structure can interfere with the normal functions of DNA, such as replication and transcription, leading to cellular death by apoptosis or necrosis. The ineffective isomer of cisplatin, transplatin (trans-[PtCl2(NH3)2]), is not able to form 1,2-intrastrand cross-links [19]. Transplatin forms only 1,3-intrastrand and interstrand cross-links and this might be the reason why transplatin is antitumor inactive [18].
In addition, a sensing system based on the photoinduced electron transfer of quantum dots (QDs) was also designed to measure the interaction of anticancer drug and DNA, taking mitoxantrone (MTX) as a model drug. The MTX adsorbed on the surface of QDs and this, can quench the photoluminescence (PL) of QDs through the photoinduced electron-transfer process, then the addition of DNA will bring the restoration of QDs PL intensity, as DNA can bind with MTX and remove it from QDs.
Cisplatin-DNA sequence selectivity has been given great attention from the research community. Several studies show that cisplatin first binds monofunctionally to guanine N7 and is particularly reactive towards Gn-runs (n ≥ 2) (Figure 7) [18, 20, 21]. The high nucleophilicity of Gn-runs attracts the positively charged cisplatin monoaqua specie. The lifetime of the monoadduct is relatively long and it has therefore been suggested that the initial monoadduct is crucial for the type of cross-linked adduct formed and thus for the cytotoxic properties of the Pt complex. The main factors influencing the mono-functional binding affinity in DNA are thought to be [18] the type of bound nucleotide and of the adjacent residues, the steric effects of the Pt complex, the hydrogen binding properties of the Pt-DNA adduct and the DNA conformation.
Assumed mechanism for the formation of cisplatin-DNA adducts.
The formation of a cisplatin adduct with the GpG bases requires a significant tilting of the bases leading to a perturbation of the regular B-DNA conformation. The structural perturbation has been shown to be specifically recognized by a number of cellular proteins, including proteins with high-mobility group (HMG) binding domains and the TATA box binding protein [22]. It is believed that (some of) these recognition proteins mediate the cellular response which finally induces cell death by apoptosis or necrosis. In some cases, relatively subtle changes in the adduct structure can affect the recognition and the biological effects in a major way. This is exemplified by the cisplatin analogue oxaliplatin which forms similar G*G*-Pt adducts as cisplatin [18]. However, the oxaliplatin-G*G adducts differ in repair efficiency, mutagenesis and translesion synthesis, believed to be related to the differential activity of the two drugs (oxaliplatin is used, in combination with 5-fluorouracil, for the treatment of colorectal cancers against which cisplatin is inactive). The evaluation of the structural details of the platinum-DNA adducts and of their effects on protein, recognition can therefore help to understand why the biological activities of two similar platinum compounds (e.g., cisplatin versus oxaliplatin) are different. So far only nine cisplatin-DNA adducts have been characterized by NMR and/or x-ray crystallography. These structures were extensively reviewed by Ano et al. and found to be basically similar in structure. The cisplatin-GG adduct kinks the double helix approx. Approximately 60 towards the major groove and induces N sugar pucker for X of 5′ XG*, 5′ G* and the C complementary to 3′ G* [18].
This metal-based compound or coordination compounds that bind to DNA have been an active area of research since the discovery of cisplatin and the platinum-based drugs. The transition-metal compounds bind to DNA through several ways and different factors that promote it, such as the intercalant ligand and the nature and position of the substituent over it. Several techniques to follow metal-based drugs interactions with DNA are used as a powerful tool in order to reach a deep knowledge of the parameters involved in the stabilization of coordination compound-DNA adduct.
DNA damaging agents (drugs that interfere with DNA function by chemically modifying specific nucleotides) includes mitomycin-C and echinomycin.
Mitomycin-C is a well-characterized antitumor antibiotic that forms a covalent interaction with DNA after reductive activation (Figure 8). The activated antibiotic forms a cross-linking structure between guanine bases on adjacent strands of DNA therefore inhibiting single strand formation [8].
Schematic interaction between DNA and mitomycin-C.
Several studies have proved that both echinomycin quinoxaline rings bisintercalate into DNA, with CG selectivity, while the inner part of the depsipeptide establishes H-bonds with the DNA bases of the minor groove region of the two base pairs comprised between the chromophores (Figure 9) [8].
Schematic interaction between DNA and echinomycin.
The addition of anticancer drugs to a DNA molecule creates a new bond. Some examples for these mechanisms include intercalating agents, intercalating reagents (II), and bleomycins.
This agent contains planar aromatic or heteroaromatic ring systems (dactinomycin as an example), binding to sugar phosphate backbone by cyclic peptide or by NH3. The planar systems slip between the layers of nucleic acid pairs and disrupt the shape of the helix. The preference is often shown for the minor or major groove. The intercalation prevents replication and transcription. In addition, the intercalation inhibits topoisomerase II (an enzyme that relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand). Another example is the intercalation of the flat part of the molecule of Adriamycin into DNA, presenting the local unwinding of the helical structure (Figure 10) [23].
Diagrammatic model illustrating intercalation of the flat part of the molecule of adriamycin (in black) into DNA, presenting the local unwinding of the helical structure.
During replication, supercoiled DNA is unwound by the helicase. The thereby created tension is removed by the topoisomerase II (topo II) that cuts and rejoins the DNA strands. When doxorubicin is bound to the DNA it stabilizes the DNA-topo (II) complex at the point where the enzyme is covalently bound (Figure 11) [1, 24].
Stabilizations of DNA-topo (II) complex.
The bleomycin A2 intercalate via the bithiazole moiety (DNA-binding domain) (Figure 12). The bithiazole moiety intercalates into the double helix and the attached side chain containing a sulfonium ion is attracted to the phosphodiester backbone. In addition, the N-atoms of the primary amines, pyrimidine ring and imidazole ring chelate Fe, which is involved in the formation of superoxide radicals, which subsequently act to cut DNA between purine and pyrimidine nucleotides [25].
The intercalating region (in blue color) of bleomycin A2 via the bithiazole moiety to DNA.
Various analytical techniques have been used for studying drug-DNA interactions (interaction between DNA and small ligand molecules that are potentially of pharmaceutical importance). Several instrumental techniques (emission and absorption spectroscopic) such as infrared (IR), UV-visible, nuclear magnetic resonance (NMR) spectroscopies, circular dichroism, atomic force microscopy (AFM), electrophoresis, mass spectrometry, viscosity measurements (viscometry), UV thermal denaturation studies, and cyclic, square wave and differential pulse voltammetry, etc., were used to study such interactions. These techniques have been used as a major tool to characterize the nature of drug-DNA complexation and the effects of such interaction on the structure of DNA. In addition, these techniques are regularly applied to monitor interactions of drugs with DNA because these optical properties are easily measured and tend to be quite sensitive to the environment. Moreover, these techniques provide various types of information (qualitative or quantitative) and at the same time complement each other to provide full picture of drug-DNA interaction and aid in the development of new drugs. In addition, the information gained from this part might be useful for the development of potential survey for DNA structure and new therapeutic reagents for tumors and other diseases. In this part of the chapter, we will focus on FT-IR, UV-Visible, NMR, AFM and viscosity measurements [5].
Fourier transform infrared (FT-IR) spectroscopy is a widely used technique to study interactions of nucleic acids (DNA and RNA) and proteins with anticancer drugs and other cytotoxic agents in solutions [26, 27]. In addition, it can generate structural information of the whole molecule in a single spectrum as a photograph of all conformations present in the sample that can distinguish among A-, B- and Z-forms of DNA, triple stranded helices, and other structural patterns. In addition, it is a powerful tool to study interactions of DNA with drugs and the effects of such interactions in the structure of DNA, and providing some insights about the mechanism of drug action. The technique is ideal for systematic studies of nucleic acids (e.g., sequence variations, covalent modifications), since it is fast, nondestructive, and requires only small amount of sample [28].
IR spectrum can be divided into four characteristic spectral ranges. The region between 1800 and 1550 cm−1 corresponds to the in-plane double bond vibrations of the nucleic bases (C〓O, C〓N, C〓C and N▬H bending vibrations of bases). These bands are sensitive to changes in the base stacking and base pairing interactions. Bands occurring in the interval 1500–1250 cm−1 assigned to vibrations of the bases and base-sugar connections are strongly related to the conformational changes of the backbone chain and glycosidic bond rotation. The range 1250–1000 cm−1 involves sugar phosphate vibrations, such as, PO2 symmetric and asymmetric stretching vibrations and C▬O stretching vibrations. These vibrations show high sensitivity to conformational changes in the backbone. The range 1000–800 cm−1 is characteristic for bands associated with vibrations of sugars which correlate with the various nucleic acid sugar puckering modes (C2’-endo and C3’-endo) [29, 30].
Due to interfering absorption bands of water at 1650 cm−1 and below 950 cm−1, spectra are generally recorded also in D2O, where these bands move to 1200 cm−1, and below 750 cm−1. Combination of results from both spectra allows obtaining a complete spectrum. The use of D2O also causes shifts in nucleic acid absorptions, resulting from deuterium exchange of labile NH protons, and these can be used to monitor H–D exchange processes. A method to remove water signals in the spectra is water subtraction, using a sodium chloride (NaCl) solution as reference. D2O is used to allow shifts in the absorption of nucleic acid in order to monitor H–D exchange processes. Four regions, each having marker bands showing either nucleic acid interactions or conformations, are presented in Figure 13 [31, 32].
The characteristics IR bands of DNA and aqueous solvents. (a) 1800–1500 cm-1 region is sensitive to effects of base pairing and base stacking; (b) 1500–1250 cm-1 region is sensitive to glycosidic bond rotation, backbone conformation, and sugar pucker; (c) 1250–1000 cm-1 region is sensitive to backbone conformation; and (d) 1000–800 cm-1 region is sensitive to sugar conformation.
The ring vibrations of nitrogenous bases (C〓O, C〓N stretching), PO2 stretching vibrations (symmetric and asymmetric) and deoxyribose stretching of DNA backbone are confined in the spectral region between 1800 and 700 cm−1. The vibrational bands of DNA at 1710, 1662, 1613 and 1492 cm−1 are assigned to guanine (G), thymine (T), adenine (A) and cytosine (C) nitrogenous bases, respectively. Bands at 1228 and 1087 cm−1 denote phosphate asymmetric and symmetric vibrations, respectively. These are the prominent bands of pure DNA, which are monitored during carboplatin-DNA interaction at different ratios. Changes in these bands are shown in Figure 14 [33]. After carboplatin addition to DNA solution, G-band at 1710 shifts to 1702–3, T-band at 1662 shifts to 1655 and A-band at 1613 shifts towards lower wave number 1609–10 cm−1. These shifting can be attributed to direct platin binding to G (N7), T (O2), and A (N7) of DNA bases. No major shifting is observed for phosphate asymmetric and symmetric vibrations indicating no external binding. The plots of the relative intensity (R i) of several peaks of DNA in-plane vibrations related to A–T, G–C base pairs and the PO2− stretching vibrations such as 1717 (G), 1663 (T), 1609 (A), 1492 (C), and 1222 cm−1 (PO2− groups), against the compound concentrations can be obtained after peak normalization using formula (1) [5, 34]:
Intensity ratio variations for DNA as a function of different carboplatin/DNA molar ratios.
where Ri is the relative intensity, Ii is the intensity of absorption peak for pure DNA and DNA in the complex with i concentration of compound, and l968 is the intensity of the 968 cm−1 peak (internal reference) [35].
Similarly, Raman spectroscopy, which also depends on characteristic group vibrational frequencies, can be used together with infrared spectra to study vibrations in DNA. It is useful because Raman and IR spectroscopy provide complementary information.
UV-visible absorption spectroscopy can be utilized to detect the DNA-ligand interaction by measuring the changes in the absorption properties of the DNA molecules or the ligand. The UV-vis absorption spectrum of DNA displays a broad band in the range of 200–350 nm in the UV region, with a maximum situated at 260 nm. The maximum is due to the chromophoric groups in pyrimidine and purine moieties responsible for the electronic transitions. The utilization of this simple and versatile technique enables an accurate estimation of the DNA molar concentration based on absorbance measurement at 260 nm. To measure the interaction between ligands and DNA, a hypochromic shift is utilized because the monitoring of the values of absorbance enables studying of the melting action of DNA. Apart from versatility, other major advantages of UV-vis absorption spectroscopy include simplicity, reproducibility, and good sensitivity [36, 37].
Binding between ligands and the molecules of DNA causes a significant change in the chemical shift of the values presented in Table 2 [32]. For example, applying thermal denaturing in order to un-stack the base-pair double-helical DNA to form two ss-DNAs is often accompanied by the 1H resonances’ downfield shift for non-exchangeable protons.
Proton type | Expected chemical shifta (ppm) | Proton type | Expected chemical shifta (ppm) |
---|---|---|---|
T5 (CH3) | 1.00–2.00 | A 2 (CH); A 8 (CH); G 8 (CH) T 6 (CH) C 6 (CH) | 6.50–8.20 |
Sugar 2′ (CH2) | 2.00–3.00 | ||
Sugar 5′ terminal (CH2) | 3.70 | ||
Sugar 5′ (CH2); 4’(CH) | 4.00–4.50 | C 4 (NH2) (H-1)b | 6.40–6.80 |
Sugar 3′ (CH) | 4.50–5.20 | C 4 (NH2) (H-2)b | 8.30–8.50 ppm |
Sugar 1′ (CH) | 5.30–6.20 | G 1 (NH) | 12.50–13.00 ppm |
C 5 (CH) | 5.30–6.20 | T 3 (NH) | 13.50–14.00 ppm |
Typical ranges of chemical shifts for 1H NMR spectra of nucleic acids.
a Chemical shifts relative to internal TSP (3-(trimethylsilyl)propionic acid).
b For Watson-Crick base pairs (CG).
The broadening of 1H NMR resonances of DNA upon addition of an appropriate minor groove binding compound is one type of evidence of complex formation in DNA 31P-NMR spectroscopy has also been used to provide important information concerning the binding of intercalators to DNA. The 31P chemical shifts are sensitive DNA conformational changes, and hence intercalating drugs cause downfield shift, while divalent cations causes up field shifts in the 31P signal [38].
Mass spectrometry (MS) has become one of the most common techniques adopted to study interactions between DNA and small ligand molecules. The ability of mass spectrometry to investigate drug-DNA interactions have been reviewed recently. The binding stoichiometry, the relative binding affinities and the binding constants for DNA double helices of various sequences may be determined. Electrospray ionization (ESI) is the most common ionization method used in the study of biomolecules due to its soft ionization. Using ESI techniques, biomolecules can be transferred from the solution to the mass spectrometer with minimal fragmentation and, so, both the mass of the DNA and the mass of the DNA-ligand complex can be determined, as the non-covalent interactions that formed the complex are not altered during the electrospray process [39, 40, 41]. Focusing on the use of ESI-MS to study complexes, MS gives a signal for each species with a different mass and so it is very straightforward to establish the stoichiometry of the complexes. ESI-MS signals enable several calculations to be performed. The number of DNA strands involved, the number of bound cations (if present) and the number of bound ligands, among others. Taking into account the structure of the nucleic acids, ESI-MS studies are performed using negative polarity. It is well known that the phosphodiester backbone of DNA is fully deprotonated under usual working conditions. In general, in order to preserve their structure, nucleic acid solutions are prepared with monovalent ions. Perylene derivatives, such as, N,N-bis-(2-(dimethylamino)ethyl)-3,4,9,10-perylenetetracarboxylic acid diimide, favor π-π interactions with the G-tetrad surface. Moreover, 5,10,15,20-tetrakis-(1-methyl-4-pyridyl)-21H,23H-porphine is an effective telomerase inhibitor, also binds to the G-quadruplex in the c-myc promoter [42].
Atomic force microscopy (AFM) can be used to distinguish proteins bound to nucleic acid templates. One of the great advantages of the atomic force microscope, particularly with respect to the imaging of biological specimens, is that it can work in fluid, so that experiments can be performed under near physiological conditions and allowing the imaging of interactions and transactions between molecules in real time [43]. AFM techniques will play a larger role in studying interactions between biological specimens, such as ligand-receptor and protein-DNA systems, and can be applied to the study of drug interactions with a variety of biological specimens [5].
Drug-DNA complexes have been studied with AFM to determine the binding force between them. This is of considerable interest since nucleic acid ligands are commonly used as anticancer drugs and in the treatment of genetic diseases. However, determining whether they bind to DNA by intercalation within major and/or minor grooves, by normal modes, or by a combination of these modes can often be difficult. AFM was used to study drug binding mode, affinity, and exclusion number by comparing the length of DNA fragments that have and have not been exposed to the drug. It is well known that if intercalative binding is occurring, the DNA strand increases in length. Moreover, the degree of lengthening is informative in determining the binding affinity and the site-exclusion number. AFM was shown to be an effective means of seeing and measuring any changes in the DNA strand. For example, when it exposed to ethidium, the DNA strand was shown through AFM to have increased in length from 3300 to 5250 nm, this indicating the intercalative mode of binding. Similarly, AFM intercalative binding studies showed the increase in the DNA strand, from 3300 to 4670 nm, upon exposure to daunomycin. This technique has also successfully been applied to new drugs in which the mode of binding was unclear. For example, exposure of 2,5-bis(4-amidinophenyl) (APF), did not produce lengthening of the DNA strands, indicating that the drug binds by non-intercalative modes. The different structural changes and binding processes of the DNA occur because of interactions with these two components [5].
DNA viscosity is sensitive to DNA length change, for this reason, its measurement upon the addition of a compound is often concerned as the least ambiguous and most critical method to clarify the interaction mode of a compound with DNA and this will provide reliable evidence for the intercalative binding mode. Relative viscosity measurements have proved to be a reliable method for the assignment of the mode of binding compounds to DNA. In the case of classical intercalation, DNA base pairs are separated in order to host the bound compound resulting in the lengthening of the DNA helix and subsequently increased DNA viscosity. On the other side, the binding of a compound exclusively in DNA grooves by means of partial and/or non-classic intercalation, under same conditions, causes a bend or kink in the DNA helix and reducing its effective length and, as a result, DNA solution viscosity is decreased, or it remains unchanged.
Figure 15 show the interaction of three Schiff base compounds of N′-substituted benzohydrazide and sulfonohydrazide derivatives: (1) N′-(2-hydroxy-3-methoxybenzylidene)-4-tert-butylbenzohydrazide, (2) N′-(5-bromo-2 hydroxy-benzylidene)-4-tert-butylbenzohydrazide and (3) N′-(2-hydroxy-3-methoxy-benzylide-ne)-4-methylbenzenesulfonohydrazide with SS-DNA [44]. This can be explained by the insertion of the compounds in between the DNA base pairs, leading to an increase in the separation of base pairs at intercalation sites and, thus, an increase in DNA length [45].
Effects of increasing amount of compounds (1–3) on relative viscosity of SS-DNA at 25 ± 0.1°C. [DNA] = 7.2 μM, r = 0, 6.9, 13.9, 20.8, 27.8.
The viscosity data show that there are at least two phases of binding between the complex and CT-DNA. At lower concentration of the complex, the viscosity first decreases and then increases at higher concentration of complex. This slow increase in viscosity is an indication of groove binding [11].
Figure 16 indicate that with increasing amount of (3-(3,5 dimethyl-phenylimino)methyl)benzene-1,2-diol (HL), the relative viscosity of DNA first remains constant and then increases [46]. This observation supports that HL bind through intercalation mode but with different affinity, i.e., also show some affinity for binding with grooves of DNA through hydrogen bonding, typically to N3 of adenine and O2 of thymine. However, strong binding is presumably due to intercalation with DNA [11].
Effects of increasing amount of HL on relative viscosity of CT-DNA at 25 ± 0.1°C. [DNA] = 2.37 × 10−5 M.
Figure 17 [47] and Figure 18 [48] shows the electrostatic binding mode of nickel and organotin(IV) complexes with DNA, respectively. The viscosity of DNA remains essentially unchanged on the addition of the nickel complexes while it decreases in case of organotin(IV) complexes [11].
(1) Effect of increasing amount of the complexes [Ni(hhmh)2], (2) [Ni(bhmh)2], (3) [Ni(ihmh)2], (4) [Ni(PPh3)(hpeh)], (5) [Ni(PPh3)(bpeh)] and (6) [Ni(PPh3)(ipeh)] on the relative viscosity of HS-DNA at 16(±0.L)°C.
(1) Effects of increasing amount of tri-n-butyltin (IV) 3-[(3′,5’dimethylphenylamino)] propanoate and (2) triphenyltin(IV) 3-[(3′,5’dimethylphenylamino)]propanoate on relative viscosity of SS-DNA at 25 ± 0.1°C, [DNA] = 1.86 × 10−4 M.
This chapter has focused on drug-DNA interactions and their study by various analytical techniques such as IR spectroscopy, viscosity measurements, MS and AFM. These techniques are used to evaluate the binding mode as well as binding strength of the complex formed between drug and DNA. The study should be useful for the development of potential survey for DNA structure and new therapeutic reagents for tumors and other diseases. Fundamentally, drugs interact with DNA through two different ways, covalent and/or non-covalent modes. Covalent binders act as alkylating agents as they alkylate the nucleotides of DNA, while, the non-covalent binders interact by three different ways: (i) intercalation, (ii) groove binding, and (iii) external binding (on the outside of the helix). Different spectroscopic techniques are generally, powerful tools to study interactions of DNA with drugs and the effects of such interactions in the structure of DNA, providing some insights about the mechanism of drug action. The binding stoichiometry, the relative binding affinities and the binding constants for DNA double helices of various sequences.
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\n\nDesired Skills:
\n\nWhat makes IntechOpen a great place to work?
\n\nIntechOpen is a global, dynamic and fast-growing company offering excellent opportunities to develop. We are a young and vibrant company where great people do great work. We offer a creative, dedicated, committed, passionate, and above all, fun environment where you can work, travel, meet world-renowned researchers and grow your career and experience.
\n\nTo apply, please email a copy of your CV and covering letter to hogan@intechopen.com stating your salary expectations.
\n\nNote: This full-time position will have an immediate start. In your cover letter, please indicate when you might be available for a block of two hours. As part of the interview process, all candidates that make it to the second phase will participate in a writing exercise.
\n\n*IntechOpen is an Equal Opportunities Employer consistent with its obligations under the law and does not discriminate against any employee or applicant on the basis of disability, gender, age, colour, national origin, race, religion, sexual orientation, war veteran status, or any classification protected by state, or local law.
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