NTM drug discovery: status, gaps and the way forward

Wu, Mu-Lu; Aziz, Dinah Binte; Dartois, Véronique; Dick, Thomas

doi:10.1016/j.drudis.2018.04.001

Cited by 218 publications

(279 citation statements)

References 196 publications

(218 reference statements)

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“…First, we show that Mab Bamboo is capable of surviving oxygen deprivation and nutrient starvation for extended periods of time in a non-replicating state and can grow as a biofilm attached to a surface. Profiling of currently used anti-Mab antibiotics in these assays shows that these physiological forms display drug tolerance, consistent with clinically observed persistence of infection (Wu et al, 2018). Finally, we employ these assays to determine activity of novel agents targeting bacterial membrane associated functions and show that these agents display "antipersister" activity, supporting the utility of these assays.…”

Section: Introductionsupporting

confidence: 63%

“…Currently used antibiotics are not effective in eradicating this infection and new, more efficacious drugs are needed. An important observation is that MIC, the standard pharmacodynamic parameter for preclinical in vitro compound prioritization, appears to be of only limited predictive value for clinical efficacy (Wu et al, 2018). Despite the availability of highly potent antibiotics in terms of MIC values, cure rates are poor.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the availability of highly potent antibiotics in terms of MIC values, cure rates are poor. Based on our drug discovery experience in tuberculosis, a disease which shows similarities in terms of pathology, we proposed recently that the compound progression flowchart for Mab drug discovery projects should include in vitro "persister assays" (Wu et al, 2018). Rapidly growing aerated nutrient-rich planktonic cultures may not reflect the predominant physiology of the bacteria growing in patients.…”

Section: Discussionmentioning

confidence: 99%

“…More efficacious antibiotics are needed to provide reliable regimens (Daniel-Wayman et al, 2019). We recently summarized status, issues, and gaps around NTM/Mab drug discovery (Falkinham, 2018;Wu et al, 2018). One major issue is the disconnect between MIC (Minimum Inhibitory Concentration) and clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

“…However, in the case of Mab disease low MIC does not translate into rapid cure. Thus, the standard MIC assay is of limited predictive value and more predictive assays are needed as secondary bacteriological potency readouts (Wu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”

Yam

Álvarez

et al. 2020

Front. Microbiol.

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Persistence of infection despite extensive chemotherapy with antibiotics displaying low MICs is a hallmark of lung disease caused by Mycobacterium abscessus (Mab). Thus, the classical MIC assay is a poor predictor of clinical outcome. Discovery of more efficacious antibiotics requires more predictive in vitro potency assays. As a mycobacterium, Mab is an obligate aerobe and a chemo-organo-heterotroph -it requires oxygen and organic carbon sources for growth. However, bacteria growing in patients can encounter micro-environmental conditions that are different from aerated nutrient-rich broth used to grow planktonic cultures for MIC assays. These in vivo conditions may include oxygen and nutrient limitation which should arrest growth. Furthermore, Mab was shown to grow as biofilms in vivo. Here, we show Mab Bamboo, a clinical isolate we use for Mab drug discovery, can survive oxygen deprivation and nutrient starvation for extended periods of time in non-replicating states and developed an in vitro model where the bacterium grows as biofilm. Using these culture models, we show that non-replicating or biofilm-growing bacteria display tolerance to clinically used anti-Mab antibiotics, consistent with the observed persistence of infection in patients. To demonstrate the utility of the developed "persister" assays for drug discovery, we determined the effect of novel agents targeting membrane functions against these physiological forms of the bacterium and find that these compounds show "antipersister" activity. In conclusion, we developed in vitro "persister" assays to fill an assay gap in Mab drug discovery compound progression and to enable identification of novel lead compounds showing "anti-persister" activity.

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Section: Introductionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”

Yam

Álvarez

et al. 2020

Front. Microbiol.

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Antitubercular Agents

Aldrich¹,

Wallis²,

Hegde³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Mycobacterium tuberculosis remains the leading cause of death due to infection in humans. Although antibiotics are available to treat drug‐sensitive M. tuberculosis infections, the increasing incidence of drug‐resistant strains is threatening our ability to gain hold of this pandemic. In addition, recent research has highlighted that even the current standard of care antibiotics face multiple obstacles for reaching therapeutic concentrations at the site of infection. In this article, we detail the current standard of care for clinical tuberculosis (TB) disease, the chemistry, mechanisms of action, and mechanisms of resistance for the antibiotics used clinically to treat TB, the growing problem of antibiotic resistance, and other challenges associated with TB treatment, and host‐directed therapies as an additional approach to treatment. This article is meant to serve as the foundation to build from as the field addresses the dire need for continued development of new therapeutic strategies to treat TB.

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Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling

Matar,

Dong,

Matta

2024

ChemMedChem

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Mycobacteria are opportunistic intracellular pathogens that have plagued humans and other animals throughout history and still are today. They manipulate and hijack phagocytic cells of immune systems, enabling them to occupy this peculiar infection niche. Mycobacteria exploit a plethora of mechanisms to resist antimicrobials (e. g., waxy cell walls, efflux pumps, target modification, biofilms, etc.) thereby evolving into superbugs, such as extensively drug‐resistant tuberculosis (XDR TB) bacilli and the emerging pathogenic Mycobacterium abscessus complex. This review summarizes the mechanisms of action of some of the surging antimycobacterial strategies. Exploiting the fact that mycobacteria are obligate aerobes and the differences between their oxidative phosphorylation pathways versus their human counterpart opens a promising avenue for drug discovery. The polymorphism of respiratory complexes across mycobacterial pathogens imposes challenges on the repositioning of antimycobacterial agents to battle the rise in nontuberculous mycobacterial infections. In silico strategies exploiting mycobacterial respiratory machinery data to design novel therapeutic agents are touched upon. The potential druggability of mycobacterial respiratory elements is reviewed. Future research addressing the health challenges associated with mycobacterial pathogens is discussed.

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NTM drug discovery: status, gaps and the way forward

Cited by 218 publications

References 196 publications

Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”

Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”

Antitubercular Agents

Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling

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