Abstract
Staphylococcus aureus is the most ubiquitous microorganism in both environment as well as animals and exists as commensal and pathogenic bacterium. In past few years it has been emerged as a superbug causing serious burden on healthcare system. This bacterium has been found to be the most resistant one toward most of the antibiotics due to its rapid structural and genetic modifications. This chapter will shed light on various types of molecular mechanisms responsible for resistance of Staphylococcus aureus showcasing how it has been emerged as a superbug. Moreover, the recent approaches which include exploring of different drug targets keeping in view the structural and functional behavior of the Staphylococcus aureus has also been discussed.
Keywords
- Antimicrobial resistance
- Staphylococcus aureus
- Superbug
- Resistance Mechanism
- Drug resistance
- Bacterial resistance
1. Introduction
2. Quorum sensing in Staphylococcus aureus
Quorum sensing is a well-known phenomenon used mainly by prokaryotes for communication among themselves [14]. Particularly in bacteria quorum sensing is monitored by a set of signaling molecules called autoinducers as density dependent variables. They are released by bacteria around their surrounding environment which up on reaching at particular concentration develop a well-coordinated response. Density of autoinducers is monitored by bacteria for tracking changes in cell number and to alter the gene expression pattern. This is also a factor that is responsible for resistance of bacteria against antibiotics [15, 16]. Quorum sensing in
3. Various resistance mechanisms of different classes of antibiotics in Staphylococcus aureus
3.1 Resistance to β-lactam antibiotics
In early 1940’s introduction of penicillin improved the outcome cases due to
3.2 Resistance to vancomycin
Vancomycin, a lipopeptide antibiotic approved by Food and Drug Administration of the United States in 1958 found in recent years that the MRSA isolates are resist to it [52]. Vancomycin works by binding to bacterial cell envelopes and inhibiting their cell wall synthesis instead of targeting protein like other antibiotics [53]. It binds to C-terminal D-Ala–D-Ala residue of the pentapeptide to inhibit the cross-bridge formation between pentapeptide and pentaglycine preventing cell wall synthesis [54]. MRSA strains shows different ranges of resistance against vancomycin according to their MIC and are named accordingly such as MRSA showing complete resistance to vancomycin is termed vancomycin-resistant
Failure in vancomycin treatment of MRSA results due to formation of intermediate-resistant isolates namely hetero resistant vancomycin-intermediate
3.3 Resistance to lipopeptide based antibiotic daptomycin
The only approved and available lipopeptide in the US in the year 2003 with in vitro bactericidal activity and an alternative to vancomycin for various MRSA infections, is daptomycin [61]. However, during the treatment, the emergence of non-susceptible MRSA strains for daptomycin has been reported [62, 63]. Even before the approval of drug, Silverman et al. observed daptomycin non-susceptible mutants and identified number of changes such as increase in membrane fluidity, increase in net positive charge over the surface, decrease in susceptibility to daptomycin-induced depolarization and low in surface binding of daptomycin in the cytoplasmic membrane of non-susceptible strains [64, 65]. Though the basis for reduction in susceptibility to daptomycin in MRSA strains has not been fully clarified [66]. The transfer and addition of positively charged lysine molecules to phosphatidyl glycerol in the cell membrane associated with the activity of enzyme lysyl-phosphatidyl glycerol synthetase is encoded by mprF gene [67], Mutation in mprF gene causes an increase of lysyl-phosphatidyl glycerol in the outer layer of the cell membrane, leading to an increased positive charge resulting in reduced susceptibility to daptomycin [68]. mprF mutations are the most common type of mutation in MRSA strains with reduced susceptibility to daptomycin (Figure 3) [69]. Several more genes are also identified which are associated with the reduced susceptibility to daptomycin such as dsp1 or asp23. The inactivation of these genes leads to reduced daptomycin susceptibility and the overexpression of single or both of the genes leads increase in susceptibility [70] whereas expression of dltA gene contributes to the staphylococcal net positive surface charge [71]. Kanesaka et al. using transmission electron microscopy, found that the some of the strains which were exposed to daptomycin which shows resistance developed an increase in the thickness of their cell wall and their thickness decreases on revert to daptomycin susceptible [72].
3.4 Resistance to aminoglycosides
Aminoglycosides works by mistranslation and changing the conformation of tRNA during bacterial protein synthesis by binding to A-site present on 16S rRNA of the 30S ribosome. Some even acts by inhibiting initiation /or elongation phase thereby blocking bacterial protein synthesis [73]. Most common mechanism of resistance to aminoglycosides especially in
3.5 Resistance to oxazolidinones
Oxazolidinones, the synthetic antibiotics blocks the formation of functional 70S initiation complex thereby preventing bacterial protein synthesis. Linezolid and tedizolid types of drugs from Oxazolidinones works interrupting transitional RNA positioning by binding to the bacterial 23S rRNA at the ribosomal peptide-transferase center. Even with the similarity in both of the structure tedizolid still shows increased and better interactions at the binding site with increased potency [78]. All these resistance mechanisms make alteration to oxazolidinone binding site, most common are the point mutations occurring in the genes encoding for 23S rRNA mostly in the central loop of domain V [79]. S. aureus has four to seven copies of 23S rRNA gene collection of which determines the effect and degree of linezolid resistance [80, 81]. This kind of mutation, G2576T, in all five copies of its 23S rRNA gene has been found in the first clinical isolates of linezolid-resistant MRSA [82] are most common. Mutations in the genes which are encoding for L3 and L4 similar to mutation in 23S rRNA, induces a change in the linezolid binding site shows linezolid resistance. Studies showed structural rearrangement of the linezolid binding site due to deletion of one amino acid in L3 causing change in the position of several of the 23S rRNA bases as targeted by point mutations. Gene cfr (chloramphenicol-florfenicol resistance) linked with various mobile genetic elements also shows resistance to linezolid and other antibiotics by change in the drug binding site at the ribosomal peptide-transferase center by encoding a rRNA methyltransferase that causes change in position A2503 [83, 84, 85]. Several bacterial species port the cfr gene, a reservoir for drug resistance. MRSA isolates with cfr genes are more likely have additional antibiotic resistance genes as compared to non-cfr gene isolates. Another gene, optrA found commonly symbiosis with cfr gene in MRSA isolates also shows resistance to oxazolidinones [84]. Acts as an ATP-binding cassette transporter, which mediate the influx and efflux of drugs. Another optrA structurally similar gene poxtA first identified in MRSA isolates, shows in vitro resistance to oxazolones [86, 87, 88, 89].
3.6 Resistance to quinolones with a focus on novel antibiotic delafloxacin
The fluoroquinolones (FQ) were first introduced into clinical practice in the year 1962 along with the development of Nalidixic acid. Fluoroquinolones (FQ) are class of fully synthetic antibiotics which are active against a broad range of gram positive and gram-negative bacteria and have a pivotal role in multidrug resistance therapy in Mycobacterial infection (Tuberculosis and non-tuberculosis). To treat acute bacterial skin and skin structure infections (ABSSSIs) with both enteral and intravenous preparations FDA approved non zwitter ionic FQ delafloxacin in 2017 [90]. Due slower MICs against S. aureus than other FQs delafloxacin has a higher barrier to resistance, it can serve as ant staphylococcal drug as monotherapy. Delafloxacin is found to be effective against multiple like Streptococcus pneumoniae, anaerobic bacteria Legionella,
3.7 Resistance to new class of antibiotics: pleuromutilins
In 1951 a compound Pleuromutilin a class of antibacterial which is isolated from a fungus called Pleurotomariids. Pleuromutilin and its natural molecule found to be effective against Gram-positive bacteria. For veterinary use Tiamulin used in livestock for the treatment of gastrointestinal and respiratory disease. Valnemulin is a second veterinary systemic Pleuromutilin antimicrobial approves and widely use in Asia and Europe. For systemic human use lefamulin was synthesized in 2006, lefamulin is novel pleuromutilin drug effective against most MRSA strains [100]. In phase 2 lefamulin was non inferior to intravenous Vancomycin. Pleuromutilin interferes with the process of protein synthesis by inhibiting the 50s subunit of the ribosome binding at site called peptidyl transfer centre [101, 102]. They specifically target the inhibition of initiation of translation. The extensive use of tiamulin and valenemulin for decades in livestock leads to MRSA strains and their mechanism of resistance to pleuromutilin are well studied. One of the resistance mechanisms involves alteration of target site on the ribosome which may require three or more mutations to develop resistant phenotype [103, 104, 105]. Resistant clones may be formed when
3.8 Resistance to mupirocin
Mupirocin was used as a decolonizing agent. It is widely used in CA-MRSA epidemic United States in 1990. But it was discovered in in 1970. Resistance to mupirocin by MRSA developed [10, 108]. Mupirocin resistance is developed due to ileS-2 gene [109]. The mupA and mupB genes responsible for resistance to mupirocin these genes encode novel isoleucyl-tRNA synthetases and can be carried out by plasmids [110]. The threes aspect of REDUCE-MRSA study was cluster-randomized trial that evaluate screening, isolation, and decolonization with chlorhexidine and mupirocin in intensive care unit patients [111]. Mupirocin is best suitable option for MRSA nasal decolonization but shows some side effects. Development of novel decolonization agent should be our propriety. We can also develop agents that can act synergistically with mupirocin as recently described [112, 113].
3.9 Resistance to lipoglycopeptides
Dalbavancin, oritavancin, and telavancin, the semisynthetic derivatives of glycopeptides are the three lipoglycopeptides available in the US. Glycopeptides usually inhibits bacterial cell wall synthesis by binding to D-alanyl-D-alanine (D-Ala-D-Ala) terminal of growing peptidoglycan chains [114]. Due to their distinctiveness in structural modifications of each drugs heptapeptide core, lipoglycopeptides are more powerful than vancomycin which contains lipid side chain that helps in holding the drug to cell membrane providing stability and an increase in concentration of local drug. In case of oritavancin and telavancin their interaction with the cell wall promotes another mechanism of action as concentration-dependent depolarization of cell membrane leading to increase in permeability. Because of the structure of oritavancin it allows several other mechanisms of action which includes binding to the secondary site in peptidoglycan chains, pentaglycyl bridging segment of lipid II, transpeptidation inhibition and RNA synthesis inhibition [115, 116]. A survey study conducted from 2010 to 2014 in US and Europe showed 99.9% isolates of S. aureus susceptible to oritavancin and 98% isolates susceptible to dalbavancin in global survey during 2002 to 2012 [117] with rare Lipoglycopeptide resistance among S. aureus. Recently for dalbavancin, Resistance in some clinical isolates has been reported. On structural analysis showed an increase in the thickening of cell wall and abnormal cell wall construction in dalbavancin non-susceptible isolates [118, 119].
4. Evolution of Staphylococcus aureus as superbug
Alexander Flaming accidently discovered penicillin as fungal contaminant also having bactericidal effect against Staphylococcus aureus which in turn led to bulk production of this antibiotic [120]. Consequently, death rate due to bacterial pneumonia and meningitis fell down during World War II. Penicillin was discovered to act by breaking peptidoglycan assembly within bacterial cell wall followed by cell death due to osmotic fragility [121]. In early 1940’s death rate of Staphylococcal infections was approximately 80%. However, resistance
5. Conclusion
The rapid evolution of resistance in
Acknowledgments
Authors are grateful to the University Grants Commission for providing NFOBC to Atamjit Singh. The authors are also thankful to Guru Nanak Dev University, Amritsar for providing various facilities to carry out the work.
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