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Targeting persisters for tuberculosis control.

ABSTRACT: Mycobacterial persisters, the survivors from antibiotic exposure, necessitate the lengthy treatment of tuberculosis (TB) and pose a significant challenge for our control of the disease. We suggest that persisters in TB are heterogeneous in nature and comprise various proportions of the population depending on the circumstances; the mechanisms of their formation are complex and may be related to those required for persistence in chronic infection. Results from recent studies implicate multiple pathways for persister formation, including energy production, the stringent response, global regulators, the trans-translation pathway, proteasomal protein degradation, toxin-antitoxin modules, and transporter or efflux mechanisms. A combination of specifically persister-targeted approaches, such as catching them when active and susceptible either by stimulating them to "wake up" or by intermittent drug dosing, the development of new drugs, the use of appropriate drug combinations, and combined chemotherapy and immunotherapy, may be needed for more effective elimination of persisters and better treatment of TB. Variations in levels of persister formation and in host genetics can play a role in the outcome of clinical treatment, and thus, these may entail personalized treatment regimens.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3346619 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Targeting persisters for tuberculosis control.

Zhang Ying Y Yew Wing Wai WW Barer Michael R MR

Antimicrobial agents and chemotherapy 20120305 5

Mycobacterial persisters, the survivors from antibiotic exposure, necessitate the lengthy treatment of tuberculosis (TB) and pose a significant challenge for our control of the disease. We suggest that persisters in TB are heterogeneous in nature and comprise various proportions of the population depending on the circumstances; the mechanisms of their formation are complex and may be related to those required for persistence in chronic infection. Results from recent studies implicate multiple pa ...[more]

PMID: 22391538

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Project description:The lengthy and complicated multidrug therapy currently available to treat active tuberculosis (TB) infection has contributed to medical non-adherence and the emerging problems of multidrug-resistant (MDR)- and extensively drug-resistant (XDR)-TB, which are particularly deadly in the setting of HIV co-infection. The prolonged therapy required to eradicate TB infection is believed to reflect the ability of Mycobacterium tuberculosis (Mtb) to persist within host necrotic granulomas in a non-replicating state characterized by antibiotic tolerance to bactericidal drugs, which predominantly target actively dividing tubercle bacilli. The stringent response enzyme, RelMtb, is essential for Mtb survival under physiologically relevant stress conditions in vitro and in the lungs of mice and guinea pigs. A library of over 2 million compounds was screened in RelMtb-inhibition assays and whole-cell screens under conditions in which RelMtb is essential. A total of 178 RelMtb inhibitor candidates, representing 18 unique scaffolds, were identified and 39 compounds were tested against nutrient-starved wild-type Mtb. The antibiotic susceptibility of a relMtb deletion mutant (Δrel) was studied during nutrient starvation and chronic infection in mice, and isoniazid and RelMtb inhibitor candidates were tested for synergy against nutrient-starved wild-type Mtb and Δrel using checkerboard assays. The minimum bactericidal concentration of isoniazid was 500-fold lower against Δrel relative to wild type during nutrient starvation, and the potent bactericidal activity of isoniazid was maintained against Δrel during chronic infection in the lungs of mice. Inhibition of RelMtb appears to be a promising new approach to target Mtb persisters, with the potential to shorten the duration of treatment for drug-susceptible and drug-resistant TB. We used microarray to characterize the transcriptomic profiles of the wild type and Δrel during nutrient starvation. The RelMtb inhibitor, (E)-4-(3-methyl-4-(2-(4-methylthiazol-5-yl)ethoxy)styryl)benzoic acid, killed wild-type Mtb and prevented isoniazid tolerance during nutrient starvation. Treatment of nutrient-starved wild-type with the RelMtb inhibitor led to downregulation of the RelMtb regulon. Transcriptomic analysis revealed an altered gene expression in Δrel and wild-type treated with RelMtb inhibitor during nutrient starvation.

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Targeting persisters for tuberculosis control.

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Targeting persisters for tuberculosis control.

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