Two Decades of TB Drug Discovery Efforts—What Have We Learned?

Bandodkar, Balachandra; Shandil, Radha; Bhat, Jagadeesh J.; Balganesh, Tanjore S.

doi:10.3390/app10165704

Cited by 15 publications

(14 citation statements)

References 96 publications

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“…In the treatment of TB, the need for new antibiotics can only be described as urgent ( Bandodkar et al, 2020 ). Phenotypic HTS of large chemical libraries using Mtb or surrogate mycobacteria provide a powerful approach for the discovery of new compounds with anti-TB activity.…”

Section: Discussionmentioning

confidence: 99%

The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds

Dal

Speth

Johann

et al. 2022

Disease Models &Amp; Mechanisms

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With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening (HTS) campaigns is a major obstacle in drug discovery. Moreover, in vivo testing using conventional animal TB models such as mice is time-consuming and costly, and represents a major bottleneck in lead compound discovery and development. Here, we report the use of the zebrafish embryo TB model, to evaluate the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently identified to possess anti-tuberculosis activity in vitro. To aid solubilization compounds were formulated in biocompatible polymeric micelles (PM). Three of the five PM-formulated nitronaphthofuran derivatives showed low toxicity in vivo, significantly reduced bacterial burden and improved survival in infected zebrafish embryos. We propose the zebrafish embryo TB-model as a quick and sensitive tool for evaluating in vivo toxicity and efficacy of new anti-TB compounds during early stages of drug development. Thus, this model is well suited to pinpoint promising compounds for further development.

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Section: Discussionmentioning

confidence: 99%

The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds

Dal

Speth

Johann

et al. 2022

Disease Models &Amp; Mechanisms

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“…1 H NMR (300 MHz, MeOD) δ 7.17 (s, 1H), 4. 24 -4.10 (m, 1H), 4.12 -3.99 (m, 1H), 3.98 -3.74 (m, 2H), 3.74 -3.46 (m, 6H), 3.40 -3.35 (m, 1H) 12,167.83,158.29,153.09 (d,J = 12.7 Hz),149.53,134.74 (d,J = 239.5 Hz),134.51,120.61,115.76,108.51,72.66,72.24,64.87,63.22,56.49 (d,J = 9.8 Hz),53.88,50.90,48.15,41.04,39.58,27.44,17.37,17. 120.80,115.49 (d,J= 3.4 Hz),108.27,93.27,92.11,72.67,72.25,64.85,56.52 (d,J= 9.6 Hz),54.77 (d,J= 23.0 Hz),46.04,39.61,31.75 (d,J= 21.7 Hz),17.37,17. (S) 4S,4',1',2,3',4,4a,4',6Hspiro[isoxazolo[4,<...…”

Section: Docking Model Generationmentioning

confidence: 99%

“…2 Among the various approaches to overcome TB drug resistance, revisiting clinically validated targets by designing next generation compounds that overcome resistance or by identifying novel scaffolds that inhibit the validated targets differently remain worthwhile approaches to explore. [3][4] Herein, we present work around the spiropyrimidinetrione (SPT) class of compounds acting through the inhibition of DNA gyrase (hereafter referred to as gyrase), a clinically validated target for the treatment of TB.…”

Section: Introductionmentioning

confidence: 99%

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

et al. 2022

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New antibiotics with either a novel mode-of-action (MoA) or novel mode-of-inhibition (MoI) are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug resistant Mycobacterium tuberculosis (Mtb), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to Phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against Mtb DNA gyrase (e.g., Compound 42 with an IC50 = 2.0) and lower Mtb MICs (0.49 µM for 42). Notably, 42 and analogues showed selective Mtb activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with Mtb DNA gyrase was developed and a structural hypothesis was built for SAR expansion.

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“…Such screens identified compounds that target growth inhibition or killing of the bacteria growing in rich media conditions. However, they typically yield similar chemical classes as hits (Bandodkar, Shandil, Bhat, & Balganesh, 2020;Kumar et al, 2017), possibly due to the same target spaces being explored. These assays do not fully capture the in vivo characteristics of Mtb such as the extreme slow growth and distinct environments and niches.…”

Section: Current Approaches In Anti-tb Drug Discoverymentioning

confidence: 99%

Advances in host‐based screening for compounds with intracellular anti‐mycobacterial activity

Subhash

Sundaramurthy

2021

Cellular Microbiology

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Intracellular pathogens interact with host systems in intimate ways to sustain a pathogenic lifestyle. Consequently, these interactions can potentially be targets of hostdirected interventions against infectious diseases. In case of tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), while effective anti-tubercular compounds are available, the long treatment duration and emerging drug resistance necessitate identification of new class of molecules with anti-TB activity, as well as new treatment strategies. A significant part of the effort in finding new anti-TB drugs is focused on bacterial targets in bacterial systems. However, the host environment plays a major role in pathogenesis mechanisms and must be considered actively in these efforts. On the one hand, the bacterial origin targets must be relevant and accessible in the host, while on the other hand, new host origin targets required for the bacterial survival can be targeted. Such targets are good candidates for hostdirected therapeutics, a strategy gaining traction as an adjunct in TB treatment. In this review, we will summarise the screening platforms used to identify compounds with anti-tubercular activities inside different host environments and outline recent technical advances in these platforms. Finally, while the examples given are specific to mycobacteria, the methods and principles outlined are broadly applicable to most intracellular infections.

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Two Decades of TB Drug Discovery Efforts—What Have We Learned?

Cited by 15 publications

References 96 publications

The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds

The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

Advances in host‐based screening for compounds with intracellular anti‐mycobacterial activity

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