anti-TB Agents Research Articles

Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5'-Triphosphate Nucleotidohydrolase.

Tuberculosis (TB) is still a threat to humans worldwide. The rise of drug-resistant TB strains has escalated the need for developing effective anti-TB agents. Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is essential for thymidylate biosynthesis to maintain the DNA integrity. In Mycobacterium tuberculosis, dUTPase provides the sole source for thymidylate biosynthesis, which also has the specific five-residue loop and the binding pockets absent in human dUTPase. Therefore, dUTPase has been regarded as a promising anti-TB drug target. Herein, we used a luminescence-based dUTPase assay to search for the inhibitors target M. tuberculosis dUTPase (Mt-dUTPase) and identified compound F0414 as a potent Mt-dUTPase inhibitor with an IC50 of 0.80 ± 0.09 μM. F0414 exhibited anti-TB activity with low cytotoxicity. Molecular docking model and site-directed mutation experiments revealed that P79 was the key residue in the interaction of Mt-dUTPase and F0414. Moreover, F0414 was shown to have stronger binding with Mt-dUTPase than with Mt-P79A-dUTPase by surface plasmon resonance (SPR) detection. Interestingly, F0414 exhibited insensitivity and weak directly binding on human dUTPase compared with that on Mt-dUTPase. All the results highlight that F0414 is the first compound reported to have anti-TB activity by inhibiting Mt-dUTPase, which indicates the potential application in anti-TB therapy.

Identification of novel benzothiopyranones with ester and amide motifs derived from active metabolite as promising leads against Mycobacterium tuberculosis.

We reported three distinct series of novel benzothiopyranones, derived from an active metabolite (M-1) of anti-TB agent 6b. These small molecules were evaluated for their biological activities against a range of Mycobacterium tuberculosis (M.tuberculosis) strains. Preliminary druggability evaluation demonstrated that M-1 showed good aqueous solubility and hepatocyte stability. Benzothiopyranones with acyl, sulfonyl and phosphoryl groups exhibited potent invitro inhibitory activity against M.tuberculosis H37Rv and low cytotoxicity. In particular, compound 3d, containing a benzoate fragment, displayed marked metabolic stability and potent invitro activity against drug-resistant tuberculosis clinical strains. Further druggability evaluation based on the identified compounds 3d, 4e and 5b is ongoing for the discovery of promising anti-TB agents.

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy.

ABSTRACTThe therapeutic repertoire for tuberculosis (TB) remains limited despite the existence of many TB drugs that are highly active in in vitro models and possess clinical utility. Underlying the lack of efficacy in vivo is the inability of TB drugs to penetrate microenvironments inhabited by the causative agent, Mycobacterium tuberculosis, including host alveolar macrophages. Here, we determined the ability of the phenoxazine PhX1 previously shown to be active against M. tuberculosis in vitro to differentially penetrate murine compartments, including plasma, epithelial lining fluid, and isolated epithelial lining fluid cells. We also investigated the extent of permeation into uninfected and M. tuberculosis-infected human macrophage-like Tamm-Horsfall protein 1 (THP-1) cells directly and by comparing to results obtained in vitro in synergy assays. Our data indicate that PhX1 (4,750 ± 127.2 ng/ml) penetrates more effectively into THP-1 cells than do the clinically used anti-TB agents, rifampin (3,050 ± 62.9 ng/ml), moxifloxacin (3,374 ± 48.7 ng/ml), bedaquiline (4,410 ± 190.9 ng/ml), and linezolid (770 ± 14.1 ng/ml). Compound efficacy in infected cells correlated with intracellular accumulation, reinforcing the perceived importance of intracellular penetration as a key drug property. Moreover, we detected synergies deriving from redox-stimulatory combinations of PhX1 or clofazimine with the novel prenylated amino-artemisinin WHN296. Finally, we used compound synergies to elucidate the relationship between compound intracellular accumulation and efficacy, with PhX1/WHN296 synergy levels shown to predict drug efficacy. Collectively, our data support the utility of the applied assays in identifying in vitro active compounds with the potential for clinical development.IMPORTANCE This study addresses the development of novel therapeutic compounds for the eventual treatment of drug-resistant tuberculosis. Tuberculosis continues to progress, with cases of Mycobacterium tuberculosis (M. tuberculosis) resistance to first-line medications increasing. We assess new combinations of drugs with both oxidant and redox properties coupled with a third partner drug, with the focus here being on the potentiation of M. tuberculosis-active combinations of compounds in the intracellular macrophage environment. Thus, we determined the ability of the phenoxazine PhX1, previously shown to be active against M. tuberculosis in vitro, to differentially penetrate murine compartments, including plasma, epithelial lining fluid, and isolated epithelial lining fluid cells. In addition, the extent of permeation into human macrophage-like THP-1 cells and H37Rv-infected THP-1 cells was measured via mass spectrometry and compared to in vitro two-dimensional synergy and subsequent intracellular efficacy. Collectively, our data indicate that development of new drugs will be facilitated using the methods described herein.

In-silico design and ADMET predictions of some new imidazo[1,2-a]pyridine-3-carboxamides (IPAs) as anti-tubercular agents

Tuberculosis (TB) is one of the leading infectious diseases worldwide even with the ravaging COVID-19 pandemic in recent times. This mandated further search and exploration of more possible anti-TB drug candidates against M. tuberculosis strains. As an extension of our previous work on the homology modeled cytochrome b subunit of the bc1 complex (QcrB) of Mycobacterium tuberculosis, an in-silico design was carried out in order to further explore more newly potential anti-TB compounds. Ligand 26 was selected as the lead template (scaffold A) based on our previous docking results and its less bulky structure. Successively, eight (8) new ligands (A1–A8) were designed with better binding affinities in comparison to the scaffold template (−6.8 kcal/mol) and isoniazid standard drug (−6.00 kcal/mol) respectively. In addition, three (3) designed ligands namely, A6, A2, and A7 with higher binding affinities were validated via ADME and toxicity prediction analysis, and the results showed zero violations of Lipinski rules with similar bioavailability, and high rate in gastrointestinal absorption, while toxicity parameters such as carcinogenicity and cytotoxicity were all predicted as non-toxic (inactiveness). The designed IPA compounds in the present study could serve as a promising gateway that could help the medicinal and synthetic chemist in the exploration of a new set of derivatives as anti-TB agents. Therefore, this research strongly recommends further experimental consideration of the newly designed IPA compounds through synthesis, in-vitro and in-vivo studies to validate the theoretical findings.

Identification of novel anti-tuberculosis agent: An in silico investigation

BackgroundMulti-drug resistance tuberculosis is chronic and highly affected to mankind. Millions of people are affected by tuberculosis and lost their lives every year. Mycobacterium tuberculosis is resistant to the most commonly used anti-TB drugs, hence new drugs need to be developed in a short time. In this direction, many chemical compounds including benzimidazole derivatives have been identified as potent anti-tb agents. MethodVarious benzimidazole derivatives were subjected to in-silico computational screening to identify the potent anti-tubercular analogues. The ADME pharmacokinetics evaluation was performed to identify the drug-like molecules. Molecular docking investigation of selected compounds was performed against Mycobacterium Tuberculosis Enoyl Reductase (Inha) with PDB ID: 2B37, 1QG6, 4TZK, and 4TZK. The common pharmacophore hypothesis was generated using the molecular docking post-processing module. ResultThe result of ADME pharmacokinetics of some compounds is very close to the drug-like properties and can be developed as good inhibitors. Molecular docking study suggests that the proposed benzimidazole and 4H-pyran derivative have better binding affinity than standard and triclosan derivatives. Results from the pharmacophore hypothesis development study also support and suggest our prediction regarding the minimum pharmacophore features required in ligands to behave as a Mycobacterium Tuberculosis inhibitor. ConclusionCoumarin, phenylurea clubbed benzimidazole moiety and pyrano[2,3-c]pyrazole derivatives have shown greater selectivity and potency towards Mycobacterium Tuberculosis. By employing a combination of ADME, docking, and pharmacophore study calculations, novel potent hits to inhibit enoyl-acp reductase were identified with the points for consideration for designing of enoyl-acp reductase inhibitor.

Proteomic Landscape of a Drug-Tolerant Persister Subpopulation of Mycobacterium tuberculosis.

Persisters are a subpopulation of bacteria that resist killing by antibiotics, even though they are genetically similar to their drug-susceptible counterpart. Like in several other bacteria, persisters are also reported in the human pathogen Mycobacterium tuberculosis (Mtb). Stochastic formation of Mtb persisters with a high level of antimicrobial tolerance set the stage for subsequent multidrug-resistant mutations. Despite significant advancement in our understanding, much remains to be learnt about the biology of this drug-recalcitrant bacterial subpopulation. Most of the information pertaining to the metabolic evolution required for emergence of drug tolerance in tuberculosis (TB) pathogens has come from transcriptional, metabolomic, and mutagenesis studies. Since proteins are the key functional molecules regulating the majority of metabolic activities in the cell, investigation of the whole-cell protein expression profile will further provide valuable insights into the physiology of Mtb persisters. We performed a quantitative proteomic analysis of Mtb H37Rv cultured under an in vitro persistence model to identify the proteomic profile of the phenotypic drug-tolerant bacterial population. Our study reveals that proteins related to intermediary metabolism and respiration, cell-wall and cell processes, lipid metabolism, information pathways, and virulence, detoxification and adaptation functional categories are primarily modulated in the persister subpopulation. Further, we demonstrate that various surface-localized mycobacterial membrane protein large (MmpL) proteins, which exhibit a high level of expression in Mtb persisters, are crucial for the mycobacterial survival during persistent growth state. A drug-induced persister subpopulation of Mtb exhibit various differentially regulated proteins that might be critical in mitigating the antimicrobial effect of drugs and can be further explored to develop novel anti-TB agents. The peptide identifications and tandem mass spectra (MS/MS) have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD013621.

DIFFERENT TYPES OF BIO ACTIVE COUMARIN DERIVATIVES AS PROMISING CANDIDATES FOR ANTI TUBERCULAR THERAPY AND THEIR STRUCTURE ACTIVITY RELATIONSHIP (SAR) STUDIES

Tuberculosis is one the most deadliest diseases. In recent years, showed drug Mycobacterium Tuberculosis resistance property which is a global threat in recent years. In order to get remedy of this disease, various kinds of novel drugs have been developed. Coumarin is a compound whose chemistry has been widely researched on. Hundreds of its derivatives have been reported from researchers across the globe. Findings amply suggest that coumarin derivatives have novel bioactive utility. Some of them have shown potent antiTB activity as well. Particularly in a country like India which is still miles away from eradicating TB and the multi-Drug resistant variety, the search for novel compounds continues to attract researchers. This review mainly represents various kinds of bio active Coumarin derivatives as signicant anti-TB agents, and their structure activity relationship.

Efficacy and safety of combined isoniazid-rifampicin-pyrazinamide-levofloxacin dry powder inhaler in treatment of pulmonary tuberculosis: A randomized controlled trial

ObjectiveTo determine the efficacy and safety of add-on dry powder for inhalation (DPI) of combined anti-TB agents prepared as a particulate system (study group) compared with placebo DPI (control group) in patients diagnosed with pulmonary TB. MethodsThis study was a randomized, placebo-controlled, double-blinded parallel design. Subjects were pulmonary TB patients, new or re-treatment, aged 18 years or older. The eligible patients were randomly allocated (1:1) to either the study group or the control group using stratified blocked randomization. The add-on DPI of combined anti-TB therapy (each capsule contained isoniazid 5 mg, rifampicin 2 mg, pyrazinamide 16 mg, and levofloxacin 2 mg) was used throughout the course of the standard oral anti-TB treatment. The primary outcome was Mycobacterium tuberculosis (MTB) sputum culture conversion measured after receiving treatment for eight weeks. Secondary outcomes were clinical signs and symptoms of pulmonary TB and adverse drug reactions (ADRs) related to anti-TB agents. The percentages of patients who achieved the primary outcome were compared (95% confidence interval). All analyses were performed using the modified intention-to-treat principle. Results91 patients were randomly allocated: 44 to the study group and 47 to the control group. Important baseline data (%peak expiratory flow rate, chest X-ray findings, resistance to anti-TB agents, renal and liver function tests) were similar between the two groups. Although the percentages of patients who achieved the primary outcome were similar in both groups (34/44 [77.3%] in the study group and (34/47 [72.3%] in the control group; relative risk [RR] 1.07, 95% CI 0.84–1.36; p = 0.589), the study group patients seemed to achieve the primary outcome earlier than the control group (22/44 [50.0%] vs 15/47 [31.9%]; RR 1.57, 95% CI 0.94–2.61; p = 0.079) at the end of week 4. Cough was significantly lower in the study group than in the control group (23/44 [52.3%] vs 43/47 [91.5%]; RR 0.57, 95% CI 0.43–0.77; p < 0.001) at week 4 of treatment. Hemoptysis was found in approximately half of each group at baseline. The percentage of patients having hemoptysis was substantially reduced at week 2 of treatment (5 [11.4%] in the study group and 11 [23.0%] in the control group, p = 0.132). Regarding safety outcomes, no dyspnea or severe ADRs were reported. Adverse events (AEs) related to oral anti-TB agents, (e.g. liver function tests) were in normal ranges in most patients in both groups during the treatment. The incidences of common AEs reported (e.g. anorexia, dizziness, numbness, arthralgia, rash, and itching) were similar between the two groups, while the incidences of nausea and vomiting were significantly lower in the study group than the control group (38.6% vs 74.5%, p = 0.001, and 43.2% vs 66.0%, p = 0.029, respectively). ConclusionsAdd-on combined anti-TB DPI therapy to the standard oral anti-TB treatment did not increase MTB sputum culture conversion at two months of treatment. However, the percentage of patients having cough in the study group was significantly lower than in the control group at two months after treatment. A reduction in cough might represent adequate response to treatment, and result in a decreased risk of spread of infection. Combined anti-TB DPI therapy was safe. Further study investigated in a larger sample using higher strengths of DPI therapy is required.

Rv0684/fusA1, an Essential Gene, Is the Target of Fusidic Acid and Its Derivatives in Mycobacterium tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major global health concern given the increase in multiple forms of drug-resistant TB. This underscores the importance of a continuous pipeline of new anti-TB agents. Drug repurposing has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, is one such candidate for repurposing. The present study aimed to understand the mechanism of action of FA and its selected analogs in M. tuberculosis. By using chemical biology and genetics, we identified elongation factor G as the target of FA in M. tuberculosis. We showed essentiality of its encoding gene fusA1 in M. tuberculosis by demonstrating that the transcriptional silencing of fusA1 is bactericidal in vitro and in macrophages. Thus, this work validated a novel drug target FusA1 in M. tuberculosis.

Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb’s differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host’s antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.

GENETIC FACTORS ASSOCIATED WITH MUTATIONS OF MOLECULAR MECHANISM AND DRUG RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS

Mycobacterium tuberculosis shows drug resistance patterns (drug-resistance tuberculosis DR-TB) for strains that are induced with high mortality rates. Because this acid-fast bacterium resists extensively against drugs and masks their effects to control the disease. However, these chromosomal mutations and genetic factors lead towards recent anti-TB drug discoveries. Anti-TB regimens are dearth to control this pandemic problem due to the high prevalence of this disease. These situations are remarkably given new ray to discover newer drugs that target such bacilli strains genetic factors and mutations. Also, it provides molecular updates to the resistance mechanism of mutations and genetic factors as a basic target then screened-out recent new anti-TB agents to limit the MDR-TB.

The largest prison outbreak of TB in Western Europe investigated using whole-genome sequencing.

BACKGROUND: In March 2011, the Department of Public Health East in Ireland were notified of two cases of TB in two prisoners sharing a cell. We define the resulting outbreak and highlight the role of public health and laboratory-based molecular epidemiology in mapping and control of a prison outbreak.METHODS: Cases were identified through clinical presentation, contact tracing, case-finding exercise or enhanced laboratory surveillance. Mycobacterium tuberculosis isolates were genotyped and underwent whole-genome sequencing (WGS).RESULTS: Of the 34 cases of TB linked to the outbreak, 27 were prisoners (79%), 4 prison officers (12%) and 3 community cases (9%). M. tuberculosis was isolated from 31 cases (culture positivity: 91%). A maximum of six single-nucleotide polymorphisms separated the isolates, with 22 being identical, suggestive of a highly infectious 'super-spreader´ within the prison. Isolates belonged to the Beijing sub-lineage, and were susceptible to first-line anti-TB agents. A case-finding exercise incidentally detected a prisoner with multidrug-resistant TB. Of the 143 prison officers screened, 52% had latent TB infection. Litigation costs exceeded five million euros.CONCLUSION: This constitutes the largest prison outbreak of TB in Western Europe investigated using WGS. A robust prison entry TB screening and education programme is required to effect better TB control, and prevent future outbreaks and attendant litigation.

Carrier Effect in Development of Rifampin Loaded Proliposome for Pulmonary Delivery: A Quality by Design Study.

Purpose: Pulmonary tuberculosis (TB) is a worldwide life-threatening infection. Therecommended anti-TB regimen contains oral administration of classical first-line drugs suchas rifampin for 6-24 months which often leads to low patient compliance due to high adverseeffects; therefore, lung localized pulmonary delivery of anti-TB agents may be a suitablealternative. Proliposomes free-flowing powders are well-known carriers for lung delivery sincethey can form liposomes by hydration. Liposomes are safe and useful carriers for lung deliverydue to their phospholipid structure. Methods: Porous lactose and mannitol as proliposome carriers were prepared by spray dryingtechnique using sucrose and citric acid as templating agents. Design Expert® software wasused to develop forty formulations based on the porous and non-porous carriers, which werecharacterized with respect to their weight yield, density, and flowability. Rifampin-loadedhydrated liposomes were produced and evaluated for size, morphology, loading capacityand encapsulation efficiency. The optimized proliposomes in vitro release and aerosolizationproperties were evaluated. Solid-state analysis was confirmed by differential scanningcalorimetry (DSC). Results: Porous lactose surface area was 80 folds higher than non-porous one, respectively.Optimized porous-based proliposome indicated the acceptable aerosolization properties,including mass median aerodynamic diameter (MMAD) of 6.21 ± 0.36 μm and fine particlefraction (FPF) of 9.17 ± 0.18% with a fast rifampin release (80%) within one hour. DSC resultsproved that there was no change in the solid-state of rifampin during the production process. Conclusion: Hence, it seems; rifampin loaded inhalable proliposomes may be a suitable systemfor delivering liposomal rifampin into the lungs.

Facile TiO2 NPs catalysed synthesis of substituted-4-Hydroxy/methoxy benzylidene derivatives as potent antioxidant and anti-tubercular agents

In this work, we report a facile synthesis of a series of substituted-4-hydroxy/methoxy benzylidene derivatives ( 3a-i ) via Knoevenagel condensation reaction of different active methylene compounds ( 1 ) with 4-hydroxy/methoxy benzaldehyde ( 2 ) under reflux condition in aq. EtOH using catalytic amount of TiO 2 NPs. The structures of all the obtained compounds were confirmed by analytical and spectroscopic methods and screened for their antioxidant and anti-tubercular activities. Antioxidant activity results revealed that, the compound 3e with IC 50 value 105.48 µg/mL showed very effective DPPH scavenging activity and compound 3h with IC 50 value 129.72 µg/mL exhibited most effective nitric oxide radical scavenging activity compared to the reference standard BHT and ascorbic acid respectively. From the results of anti-TB activity, compound 3b displayed a more sensitivity at 25 µg/mL. Furthermore, synthesized compounds were assessed for molecular docking studies on the target enzymes Human peroxiredoxin 5 and enoyl-ACP reductase and they were emerged has an active antioxidant and anti-TB agents with least binding energy -5.8 and -8.0 kJ mol −1 respectively.

Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis.

Tuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ combination partially restored SPT efficacy against an SPT-resistant mutant carrying a g1379t point mutation in rrs, encoding the mycobacterial 16S ribosomal RNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G, exhibited potentiating activity against wild-type M. tuberculosis Moreover, this combination produced a modest potentiating effect against both FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-TB agents, rifampicin (RIF) and isoniazid, resulted in enhanced activity in vitro and ex vivo against both drug-susceptible M. tuberculosis and a RIF-monoresistant rpoB S531L mutant.These results support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of M. tuberculosis strains carrying genetic resistance to any one of the partner compounds.

Design, synthesis and biological activity of N-(amino)piperazine-containing benzothiazinones against Mycobacterium tuberculosis.

A series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent invitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: < 0.016μg/mL), and good safety index (CC50: >64μg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compound for future antitubercular drug discovery.

The M. tuberculosis Rv1523 Methyltransferase Promotes Drug Resistance Through Methylation-Mediated Cell Wall Remodeling and Modulates Macrophages Immune Responses.

The acquisition of antibiotics resistance is a major clinical challenge limiting the effective prevention and treatment of the deadliest human infectious disease tuberculosis. The molecular mechanisms by which initially Mycobacterium tuberculosis (M.tb) develop drug resistance remain poorly understood. In this study, we report the novel role of M.tb Rv1523 MTase in the methylation of mycobacterial cell envelope lipids and possible mechanism of its contribution in the virulence and drug resistance. Initial interactome analyses predicted association of Rv1523 with proteins related to fatty acid biosynthetic pathways. This promoted us to investigate methylation activity of Rv1523 using cell wall fatty acids or lipids as a substrate. Rv1523 catalyzed the transfer of methyl group from SAM to the cell wall components of mycobacterium. To investigate further the in vivo methylating role of Rv1523, we generated a recombinant Mycobacterium smegmatis strain that expressed the Rv1523 gene. The M. smegmatis strain expressing Rv1523 exhibited altered cell wall lipid composition, leading to an increased survival under surface stress, acidic condition and resistance to antibiotics. Macrophages infected with recombinant M. smegmatis induced necrotic cell death and modulated the host immune responses. In summary, these findings reveal a hitherto unknown role of Rv1523 encoded MTase in cell wall remodeling and modulation of immune responses. Functional gain of mycolic acid Rv1523 methyltransferase induced virulence and resistance to antibiotics in M. smegmatis. Thus, mycolic acid methyltransferase may serve as an excellent target for the discovery and development of novel anti-TB agents.

Contribution of N-heterocycles towards anti-tubercular drug discovery (2014-2019); predicted and reengineered molecular frameworks.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, responsible for high death frequency every year all over the world. In this regard, efficient drug-design and discovery towards the prevention of M.tb H37 Rv is of prime concern. Prevention of the infection may include vaccination, and the treatment comprises anti-TB drug regimen. However, the vaccine decreases the risk of tuberculosis infection only to some extent, while drug-resistance limits the efficacy of the existing anti-TB agents. Much improvement has to be achieved to overcome pitfalls such as side effects, high-toxicity, low bioavailability, pharmacokinetics and pharmacodynamics, and hence forth in clinical therapeutics. Amongst heterocyclic compounds, N-heterocycles played a pivotal role in drug-design and discovery. A wide range of microbial diseases are being treated by the N-heterocyclic drugs. The present review comprises description of anti-TB effects of the N-heterocycles such as indoles, triazoles, thiazoles, and pyrazoles. The potent anti-TB activity exerted by the derivatives of these heterocycles is evaluated critically alongside emphasizing structure-activity relationship. Besides, docking studies supporting anti-TB activity is supplemented. Alongside this, based on the potent heterocyclic molecules, the molecular frameworks are designed that would bring about enhanced M. tb H37 Rv inhibitory potencies.

Easy-To-Access Quinolone Derivatives Exhibiting Antibacterial and Anti-Parasitic Activities.

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24–31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4–20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.

Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis.

Tuberculosis (TB) is currently the leading cause of death related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of multidrug-resistant tuberculosis (MDR-TB) cases has alarmed health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In this study, 23 new compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-N-oxide (5 b) was particularly remarkable in this regard as it demonstrated MIC90 values below 0.28 μM against all the MDR strains evaluated, thus suggesting that this compound might have a different mechanism of action. Benzofuroxans are an attractive new class of anti-TB agents, exemplified by compound 5 b, with excellent potency against the replicating and drug-resistant strains of M. tuberculosis.