Noise in a Metabolic Pathway Leads to Persister Formation in Mycobacterium tuberculosis

Quigley, Jeffrey; Lewis, Kim

doi:10.1128/spectrum.02948-22

Cited by 8 publications

(6 citation statements)

References 59 publications

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“…Other studies on single cells reported that Mtb persisters are rare low-energy cells formed stochastically during normal growth [ 48 ]. Stochastic variations may occur in the expression of an energy-generating component.…”

Section: Persister Cellsmentioning

confidence: 99%

Eradication of Drug-Tolerant Mycobacterium tuberculosis 2022: Where We Stand

et al. 2023

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The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions, ranging from solid and well-vascularized cellular granulomas to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) intracellular bacilli, while in low-vascularized caseous granulomas the low-oxygen tension stimulates aerobic and microaerophilic AR bacilli to transit into non-replicating (NR), drug-tolerant and extracellular stages. These stages, which do not have genetic mutations and are often referred to as persisters, are difficult to eradicate due to low drug penetration inside the caseum and mycobacterial cell walls. The sputum of TB patients also contains viable bacilli called differentially detectable (DD) cells that, unlike persisters, grow in liquid, but not in solid media. This review provides a comprehensive update on drug combinations killing in vitro AR and drug-tolerant bacilli (persisters and DD cells), and sterilizing Mycobacterium tuberculosis-infected BALB/c and caseum-forming C3HeB/FeJ mice. These observations have been important for testing new drug combinations in noninferiority clinical trials, in order to shorten the duration of current regimens against TB. In 2022, the World Health Organization, following the results of one of these trials, supported the use of a 4-month regimen for the treatment of drug-susceptible TB as a possible alternative to the current 6-month regimen.

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Section: Persister Cellsmentioning

confidence: 99%

Eradication of Drug-Tolerant Mycobacterium tuberculosis 2022: Where We Stand

et al. 2023

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“…Additionally, it was recently reported that stochasticity associated with acetate kinase essential for acetate to enter the Krebs cycle mediates persistence in M. tuberculosis [177]. In Bacillus subtillis , the noise-driven ComKS system regulates competence and growth arrest, imposing a triggered persistence [178].…”

Section: Is Persister Formation Stochastic Deterministic or Both?mentioning

confidence: 99%

Bacterial survivors: evaluating the mechanisms of antibiotic persistence

Shi¹,

Zarkan

2022

Microbiology

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Bacteria withstand antibiotic onslaughts by employing a variety of strategies, one of which is persistence. Persistence occurs in a bacterial population where a subpopulation of cells (persisters) survives antibiotic treatment and can regrow in a drug-free environment. Persisters may cause the recalcitrance of infectious diseases and can be a stepping stone to antibiotic resistance, so understanding persistence mechanisms is critical for therapeutic applications. However, current understanding of persistence is pervaded by paradoxes that stymie research progress, and many aspects of this cellular state remain elusive. In this review, we summarize the putative persister mechanisms, including toxin–antitoxin modules, quorum sensing, indole signalling and epigenetics, as well as the reasons behind the inconsistent body of evidence. We highlight present limitations in the field and underscore a clinical context that is frequently neglected, in the hope of supporting future researchers in examining clinically important persister mechanisms.

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“…Only a few drug targets and inhibitors of nonreplicating or persistent Mtb have been identified to date, and identification of new molecular targets is a high priority for TB drug development . The persistent state of Escherichia coli and Mtb is accompanied and may be caused by low ATP levels, which could specifically sensitize ATPases to inhibition by ATP binding site-directed compounds. , …”

Section: Introductionmentioning

confidence: 99%

“…7 The persistent state of Escherichia coli and Mtb is accompanied and may be caused by low ATP levels, which could specifically sensitize ATPases to inhibition by ATP binding site-directed compounds. 8,9 Besides the direct targeting of tolerant and persistent bacteria, another strategy to combat drug resistance is hostdirected therapy (HDT) since the bacterium cannot genetically develop resistance by altering the host drug target. 10 HDT can have the dual benefit of contributing to direct clearance of infection and restricting destructive inflammation, a major cause of morbidity in TB.…”

Section: ■ Introductionmentioning

confidence: 99%

Dual Inhibition of Mycobacterium tuberculosis and the Host TGFBR1 by an Anilinoquinazoline

Nandakumar,

Ollodart,

Fleck

et al. 2023

J. Med. Chem.

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Tuberculosis (TB) control is complicated by the emergence of drug resistance. Promising strategies to prevent drug resistance are the targeting of nonreplicating, drug-tolerant bacterial populations and targeting of the host, but inhibitors and targets for either are still rare. In a cell-based screen of ATP-competitive inhibitors, we identified compounds with in vitro activity against replicating Mycobacterium tuberculosis (Mtb), and an anilinoquinazoline (AQA) that also had potent activity against nonreplicating and persistent Mtb. AQA was originally developed to inhibit human transforming growth factor receptor 1 (TGFBR1), a host kinase that is predicted to have host-adverse effects during Mtb infection. The structure−activity relationship of this dually active compound identified the pyridyl-6-methyl group as being required for potent Mtb inhibition but a liability for P450 metabolism. Pyrrolopyrimidine (43) emerged as the optimal compound that balanced micromolar inhibition of nonreplicating Mtb and TGFBR1 while also demonstrating improved metabolic stability and pharmacokinetic profiles.

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Noise in a Metabolic Pathway Leads to Persister Formation in Mycobacterium tuberculosis

Cited by 8 publications

References 59 publications

Eradication of Drug-Tolerant Mycobacterium tuberculosis 2022: Where We Stand

Eradication of Drug-Tolerant Mycobacterium tuberculosis 2022: Where We Stand

Bacterial survivors: evaluating the mechanisms of antibiotic persistence

Dual Inhibition of Mycobacterium tuberculosis and the Host TGFBR1 by an Anilinoquinazoline

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