The present state of the tuberculosis drug development pipeline

Libardo, M. Daben J.; Boshoff, Helena I.; Barry, Clifton E.

doi:10.1016/j.coph.2018.08.001

Cited by 73 publications

(68 citation statements)

References 72 publications

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“…There is an urgent need for new antimycobacterial agents preferably with novel mechanisms of action in order to tackle drug‐resistant M. tuberculosis infection . This work shows that azaaurones and their N ‐acetyl counterparts represent a new entry in the toolbox of chemotypes capable of inhibiting M. tuberculosis growth.…”

Section: Resultsmentioning

confidence: 96%

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

et al. 2019

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Herein we report the screening of a small library of aurones and their isosteric counterparts, azaaurones and N‐acetylazaaurones, against Mycobacterium tuberculosis. Aurones were found to be inactive at 20 μm, whereas azaaurones and N‐acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC99 values ranging from 0.4 to 2.0 μm. In addition, several N‐acetylazaaurones were found to be active against multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) clinical M. tuberculosis isolates. The antimycobacterial mechanism of action of these compounds remains to be determined; however, a preliminary mechanistic study confirmed that they do not inhibit the mycobacterial cytochrome bc1 complex. Additionally, microsomal metabolic stability and metabolite identification studies revealed that N‐acetylazaaurones are deacetylated to their azaaurone counterparts. Overall, these results demonstrate that azaaurones and their N‐acetyl counterparts represent a new entry in the toolbox of chemotypes capable of inhibiting M. tuberculosis growth.

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Section: Resultsmentioning

confidence: 96%

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

et al. 2019

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“…Studies have shown that the usage of the drug for drug-resistant TB treatment improved sputum conversion and reduced chemotherapy duration and relapse [16][17][18][19]. Hence, new BDQ-containing drug regimens are currently being explored in Phase III clinical trials, such as the STREAM and SimpliciTB trials [20]. One such trial, the Nix-TB trial, resulted in the recent US FDA approval of the BDQ-pretomanid-linezolid six months, all-oral regimen for the treatment of drug-resistant TB [21,22].…”

mentioning

confidence: 99%

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

2019

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Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme's c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme's catalytic α 3 β 3 -headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme's ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α 3 β 3 -headpiece. However, this mechanism is controversial as the drug's binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ's mechanisms of action. In this review, we first summarize discoveries on BDQ's mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ's anti-mycobacterial activity.Concentration (MIC) of 0.002-0.013 µg/mL [10,11]). This potent activity holds true in vivo where BDQ has demonstrated accelerated sterilizing activity [12], with four months of BDQ treatment being as efficacious as six months of first-line drug treatment of Mtb-infected mice [13]. Importantly, BDQ also displays bactericidal activity against non-replicating Mtb at therapeutically attainable concentrations [14,15]. In the clinical setting, the usage of BDQ has produced promising results. Studies have shown that the usage of the drug for drug-resistant TB treatment improved sputum conversion and reduced chemotherapy duration and relapse [16][17][18][19]. Hence, new BDQ-containing drug regimens are currently being explored in Phase III clinical trials, such as the STREAM and SimpliciTB trials [20]. One such trial, the Nix-TB trial, resulted in the recent US FDA approval of the BDQ-pretomanid-linezolid six months, all-oral regimen for the treatment of drug-resistant TB [21,22].

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“…Those pioneering compounds can lead the way to more valuable therapeutics. Numerous new compounds are being studied that either derive from the known hits or target other biosynthetic pathways of the cell wall [261,262]. In the past 20 years, M. tuberculosis has been unraveling many of its secrets: its niches in the host, its metabolism and its way of fighting drugs.…”

Section: Resultsmentioning

confidence: 99%

Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs

Vilchèze

2020

Applied Sciences

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Eighty years after the introduction of the first antituberculosis (TB) drug, the treatment of drug-susceptible TB remains very cumbersome, requiring the use of four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) for two months followed by four months on isoniazid and rifampicin. Two of the drugs used in this “short”-course, six-month chemotherapy, isoniazid and ethambutol, target the mycobacterial cell wall. Disruption of the cell wall structure can enhance the entry of other TB drugs, resulting in a more potent chemotherapy. More importantly, inhibition of cell wall components can lead to mycobacterial cell death. The complexity of the mycobacterial cell wall offers numerous opportunities to develop drugs to eradicate Mycobacterium tuberculosis, the causative agent of TB. In the past 20 years, researchers from industrial and academic laboratories have tested new molecules to find the best candidates that will change the face of TB treatment: drugs that will shorten TB treatment and be efficacious against active and latent, as well as drug-resistant TB. Two of these new TB drugs block components of the mycobacterial cell wall and have reached phase 3 clinical trial. This article reviews TB drugs targeting the mycobacterial cell wall in use clinically and those in clinical development.

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The present state of the tuberculosis drug development pipeline

Cited by 73 publications

References 72 publications

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs

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