Infectious diseases originate from pathogens and increased severely in current years. Despite numerous important advances in antimicrobial therapy, the extensive use and misuse of these antimicrobial drugs have caused the emergence of microbial resistance, which is a serious risk to public health. In particular, the emergence of multidrug-resistant pathogens has become a serious difficulty in the therapy of pathogenic diseases. Therefore, the progress of novel drugs to deal with resistant pathogens has become one of the most essential areas of antimicrobial research today. In addition to the development of novel and efficient antimicrobial agents against multidrug-resistant pathogens, recent attention has focused on the treatment of tuberculosis. Therefore, recent developments have been directed towards examining currently used and newly developed antimycobacterial drugs and their toxicities and mechanism of action.
Tuberculosis (TB) is a chronic infectious and zoonotic disease caused by the
2. Etiology and routes of transmission
Tuberculosis (TB) is caused by the
The current opinion disclosed that one-third of the 42 million people living with HIV/AIDS all around the world are co-infected with TB. As per the WHO report, about 90% of the patients containing both TB and HIV died within only some months after clinical indications have arisen. Thus, WHO warned the world of the “even bigger TB-HIV crisis” and explained for extensive accessibility of free anti-TB drugs to individuals living with HIV. The HIV cases are spreading quickly in India with the biggest number of TB cases all around the world [12, 13, 14, 15].
3. Chemotherapy of tuberculosis
Treatment of TB is mainly dependent on first-line anti-TB drugs (Figure 1), which comprises SM, INH, RMP, EMB, and PZA, these are more effective and less toxic effects as compare to second-line anti-TB drugs .
According to the WHO, there are six drugs of second-line anti-TB drugs. These drugs are categorized as second-line anti-TB drugs due to one of two potential reasons: 1) they are less active than the first-line anti-TB drugs or more toxic side-effects or 2). These drugs involve different classes namely, aminoglycosides (Figure 1): (kanamycin, amikacin), polypeptide analogs (Figure 2): (viomycin, capreomycin), FQs (Figure 3): (CPX, MXF, OFX, etc), thioamides: (prothioamide, ethionamides), cycloserine and para-aminosalicylic acid (Figure 4) [2, 3, 4].
Clarithromycin (Figure 5) is a macrolide antibiotic drug used in HIV infected TB patients to cure the
4. Properties and mechanism of currently used common anti-TB drugs
4.1 Primary agents
It is a bacteriostatic drug against resting cells and bactericidal against dividing microorganisms. Isoniazid (INH) is an anti-TB drug since 1952 and acts as a bactericidal and bacteriostatic for rapidly and slowly growing bacilli. It diffuses across the
Rifampicin (RIF) was isolated from
Rifampin is a semisynthetic analog of rifamycin and the most effective anti-TB agent with MIC values as low as 0.005 μg/mL. It is used as an oral or parenteral formulation, it can access CNS and it is sensitive to moisture [2, 3, 4].
Rifapentine is a cyclopentyl analog of RIF. The benefit over rifampin is less repeated dosing. It inhibits bacterial DNA-dependent RNA polymerase and binds to the β subunit. The RIFs blocks the elongation of the RNA transcript and inhibits gene expression. It also acts as a CYP450 inducer. One remarkable side effect is the discoloration of body fluids. The RIFs are not suggested for use in HIV infected patients. Two RIF analogs are existing for indications other than TB [2, 3, 4].
Ethambutol (EMB) is a bacteriostatic, active against growing bacilli, and used as an anti-TB drug in 1966. It obstructs polymerization of cell wall component lipoarabinomannan and arabinogalactan that interrupted biosynthesis of darabinofuranosyl-P-decaprenol and produced bacteriostatic effect [25, 26]. EMB (+) isomer is orally active, 16 times more potent than meso isomer, and 200 times more potent than (−) isomer. The EMB inhibits the polymerization of cell wall arabinan and results in the addition of the lipid carrier deca-prenol phosphoarabinose. The EMB interferes with the transfer of arabinose to the cell wall acceptors. EMB is effective only towards energetically dividing cells and its action is synergistic with RIF. Arabinosyl transferase enzyme is a target for the action of EMB in both
Pyrazinamide (PZA) is a pyrazine derivative of nicotinamide and its mechanism is assumed to be analogous to INH. It has to be metabolically activated and PZA-resistant strains of
Streptomycin (STR) is the first antibiotic cure for TB and it is isolated from the soil microbe
Para-aminosalicylic acid (PAS) is an oral drug that fell out of use because of adverse effects and frequent resistance. Related to sulfonamides, it is bacteriostatic and acts as a competitive inhibitor of mycobacterial dihydropteroate synthase. There are two mechanisms to produce the desired effect. First, it inhibited folic acid synthesis by the inhibiton of dihydrofolate synthase and dihydropteroate synthase that produces hydroxyl dihydrofolate antimetabolite responsible for the folic acid synthesis . Secondly, it reduced the uptake of iron, that is essential for cell wall component mycobactin synthesis .
Ethionamide (ETH) is developed as a derivative of INH but less potent than INH. Two genes play a role in the mechanism of actions ETH is ethA and inhA. EthA is regulated by the transcriptional repressor ETH . The mechanism of action is like INH. The oxidative activation comes into sight it is by an enzyme other than KatG projected to form a covalent connection with InhA. The mechanism of action of the ETH is a disruption of mycolic acid synthesis by which monooxygenase enzyme activated ETH that binds to NAD+ and forms an adduct which inhibits enoyl acyl-ACP reductase enzyme [37, 38, 39] (Figure 6).
Cycloserine (CYS) is a natural compound and restricted to being retreatment because of CNS toxicity. CYS is a cyclic derivative of serine hydroxamic acid and terizidone. It is isolated from
Fluoroquinolones (FQs) are the derivative of chloroquine in the 1960s and were used as bactericidal in human and veterinary medicines . The FQs are acted by blocking of mycobacterial DNA replication by binding to α and β subunits of DNA gyrase (gyrA and gyrB), which catalyze the supercoiling of DNA and finally, inhibits DNA synthesis .
The aminoglycosides (amikacin, kanamycin) and polypeptides (capreomycin, viomyocin) act by inhibiting protein synthesis. Kanamycin and amikacin alter 16S rRNA and capreomycin and viomycin interfere with small and large subunits of the 70S ribosome [44, 45].
Capreomycin belongs to the tuberactinomycin family, a highly basic cyclic pentapeptide with a sixth amino acid side chain. It is the most active compound of this family and blocks protein synthesis and interferes with initiation tRNA selection and chain elongation. It binds to a site on 16S rRNA and the 23S rRNA. Some mycobacterium resistant to capreomycin is also resistant to kanamycin [2, 3, 4].
Linezolid is an oxazolidinone derivative that interrupts the early stage in protein synthesis by binding to the 23S rRNA of the 50S subunit. The gene rplC and rrl are concerned in the action of Linezolid. The rplC gene that encodes 50S ribosomal L3 protein to involve in the synthesis of the ribosomal peptidyltransferase. Hence, rrl gene has 3138 bp length that encodes 23S ribosomal RNA .
5. Compounds originating from existing families of drugs
Fluoroquinolones (FQs) were established into clinical applications in the 1980s and extensively used for the treatment of various bacterial infections . The FQs have been also originated to have anti-TB activity  and are presently used as second-line anti-TB drugs. Cross-resistance has been accounted for within the FQs class such that reduced vulnerability to one FQ possibly presented reduced vulnerability to all FQ derivatives [49, 50, 51]. With the extensive use of FQSs for the therapy of common microbial infection, resistance to FQs remains uncommon and occurs mostly in MDR strains. The cross-resistance was observed among the various FQ compounds tested (OFX, LVX, GAT, MXF, and CPX) . The rapid progress of resistance is mostly when FQs are used as the only active drugs in a failing multi-drug therapy [53, 54, 55]. These new agents are currently taken in concern as anti-TB drugs.
Gatifloxacin (GAT) has bactericidal activity against
A series of 8-methoxy non-fluorinated quinolone analogs (NFQs) lack a 6-fluorine atom in their quinolone ring distinguishing them from fluorinated quinolone compounds such as GAT and MXF. The NFQs target a broad range of bacteria and they appear to operate preferentially through inhibition of DNA gyrase. The NFQs are presently being tested against
The anti-TB effect of the macrolide antibiotics through the synthesis of additional chemically modified analog of erythromycin. Some analog were recognized as anti-TB agent superior to the clarithromycin [4, 15].
Rifalazil, a semisynthetic RIF, is described by a long half-life and is more effective than RIF and rifabutin against
Bedaquiline is a diarylquinoline and used bactericidal. Bedaquiniline involves blocking the proton pump of ATP synthase of
Delamanid is a dihydro-nitroimidazooxazole derivative and activated by deazaflavin-dependent nitroreductase enzyme (Rv3547). It acts by interrupting the mycobacterial cell wall component synthesis. Delamanid inhibits the methoxy- and keto-mycolic acid synthesis which is a vital component of the
PA-824 is a nitroimidazole derivative and it activated by deazaflavin-dependent nitroreductase like delamanid. Mechanism of action is not clearly konown but it could be described as its activity in replicating and non-replicating mycobacteria. In aerobically replicating cell PA-824 interrupts mycolic acid synthesis by the collecting of hydroxymycolates instead of ketomycolates [70, 71]. In hypoxic non replicating mycobacteria, PA-824 release nitric oxide (NO) that interferes with cytochrome oxidase to disrupt the energy metabolism of the cell wall .
SQ-109 is an ethambutol analog and its mechanism of action is not known. It has no inhibitory activition against the secreted Ag85 mycolyltransferase. Rather SQ-109 causes collection of trehalose monomycolate a precursor of trehalose dimycolate by obstructing accumulates of mycolic acids into the
To investigating useful drug candidate’s currently in two major categories: Novel chemical entity and compounds instigating from existing relatives of currently used drugs, where novel chemistry is used to optimize the new compounds.
In this series, the lead molecules are CGI 17341 and PA824/PA1343 and inhibit the cell wall synthesis. However, two key areas of concern also require to attend-possible mutagenicity resulting from the presence of a nitro group, and the chance for the development of drug resistance. The latter is encouraged by the reality that the nitroimidazoles induce a high rate of mutation [2, 3, 4], leading to uncertainties that this might cause the appearance of MDR bacteria. Since the drugs will certainly be used in combination therapy .
The PA-824 is a nitroimidazole derivative and used as anti-TB agent. PA-824 acts mainly as synthesis of cell wall components inhibitor.
The CGI 17341 has substantial potential as anti-TB agent in a preclinical study.
It is mycolic acid inhibitors and interferes with the biosynthesis of the mycobacterial cell wall.
Miconazole is a well-known antifungal drug that has been accounted for to have anti-TB activity
A series of imidazo(4,5-c)pyridines, one compound (
Diarylquinolines (DARQs) is structurally unlike both FQs and other quinolines derivatives. The DARQ R207910 is a new class of anti-TB drugs. It has specificity towards mycobacteria as well as atypical species, important in humans such as MAC,
Diarylquinoline (DRQ) TMC207 is an exceptionally promising class of anti-TB drugs. About, 20 compounds of the DRQ series have been exhibited a MIC value below 0.5 μg/ml against
The 9-Benzylpurines, with a variety of substituents on 2, 6, and/or 8 positions, have high inhibitory activities against
The 9-benzylpurines, 2-chloro-4(2-furanyl)-9-benzylpurine was potently inhibited
Naturally occurring (5
This has led to the hope that inhibitors of the TLM target enzyme, FAS-II, are potentially important in the treatment of malaria , trypanosomiasis, or sleeping sickness , and a range of bacterial indications including TB. It also blocks long-chain mycolate synthesis in a dose-dependent mode . The TLM is active
The antimalarial agent mefloquine and its analogs have activity against a range of bacteria including
Some 2,4-diamino-5-deazapteridine derivatives, SRI-20094 has potent inhibition of MM6 cells infected with MAC strain NJ3440 with a MIC value 0.13 μg/ml. SRI-20094 inhibits the dihydrofolate reductase (DHFR) of the MAC, with an IC50 value 1.0 nM as compared to 4100, 1.4 and 1.0, nM for the trimethoprim, piritrexim, and trimetrexate,. It confirmed limited inhibition for human DHFR having an IC50 value 7300 nM. SRI-20094 is a value for the
The 1,2,4-benzothiadiazine dioxides have a close relation to sulfonamide and could be considered as cyclic sulfonamides. These compounds exhibited antimicrobial activity . The 1,2,4-benzothiadiazines were explored by incorporating other heterocyclic rings like pyridine and pyrazine moieties (
Several other molecules like pyrroles (
Marine products gorgonian coral
Tryptanthrin is an indoloquinazolinone containing alkaloid and evaluated against different strains of
The tetramethyl piperidine substituted phenazines B4169 and B4128 (TMP phenazines) have possessed significantly activity against
The B4157 is a phenazinamine derivative, closely related to clofazimine, has a potential action for TB.
Some analogs of toluidines have attractive
The arabinose disaccharide SR-9581 is
The Oxazolidinones are a class of broad-spectrum antibiotic compounds. They inhibit protein synthesis through binding to the 50S subunit of ribosomes. Oxazolidinones had considerable activities against
They have bacteriostatic activity against various human pathogens together with drug-resistant microorganisms [109, 110]. The oxazolidinones have activity against
Calanolide A is a naturally pyranocoumarin that has double action against TB and HIV infections. This compound is an inhibitor of the HIV-1 reverse transcriptase enzyme. It also exhibits good in vitro effects towards
Poloxamer 315 is a methyl oxirane surfactant polymer that shows to disrupt the cell membranes of microorganisms or their intracellular components. The purified polymer is effective against
The anthelmintic drug niclosamide was found to have anti-TB activity
The liposome-encapsulated drug for the anti-TB activity, Mikasome, is useful against
A series of fullerene analogs, compound (
Some pyrroles analogs were effective
Dipiperidine SQ-609 is structurally dissimilar to the existing anti-TB drug. It destroyed
The pleuromutilins is a novel natural antibiotic. They interfere with protein synthesis by binding to the 23S rRNA and consequently inhibiting the formation of a peptide bond . The cross-resistance might happen between pleromutilins and oxazolidinones . Pleuromutilins have been revealed to in-vitro inhibition of the
The FAS20013 belongs to the β-sulphonylcarboxamide analogs. FAS20013 destroys more organisms in a 4-hour exposure than INH or RIF can throughout a 12- to 14-day exposure. This compound is especially effective in killing MDR-TB strains that are resistant to currently used multiple drugs. The greater effect of FAS20013 compared to current anti-TB drugs in terms of its ability to sterilize TB injuries and kill latent TB strains. The FAS20013 has its efficiency in mice with no serious adverse effects and it is up to 100% bioavailable when orally used. The compound is acted by inhibition of ATP synthase .
Diamine SQ-109 was developed as a second-generation drug from the first-line drug ethambutol (EMB). When examined in a low-dose infection model of TB in mice, SQ-109 at 1 mg/kg was as efficient as EMB at 100 mg/kg. However, SQ-109 did not prove improved efficacy at higher doses (10 mg/kg; 25 mg/kg) and was less efficient than INH . The SQ-109 is effictive against MDR-TB, together with those that are EMB-resistant.
Tuberculosis (TB) is a chronic infectious disease caused by