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Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis.

ABSTRACT: Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above-mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis.

SUBMITTER: Zhang M

PROVIDER: S-EPMC3486556 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis.

Zhang Ming M Sala Claudia C Hartkoorn Ruben C RC Dhar Neeraj N Mendoza-Losana Alfonso A Cole Stewart T ST

Antimicrobial agents and chemotherapy 20120827 11

Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), ...[more]

PMID: 22926567

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Project description:Introduction: Tuberculosis (TB) is a serious human disease caused by the bacterium Mycobacterium tuberculosis (Mtb). One third of the world’s population is estimated to be latently infected with Mtb. Exact mechanisms and properties of latent TB infection (LTBI) are not fully elucidated. In essence, the pathogen can enter a dormant or latent state characterized by limited growth and metabolism, resulting in absence of clinical symptoms in the host, and most importantly by increased phenotypic tolerance to the commonly used medications, thereby allowing indefinite persistence in the human body. This persistence is the main reason why the current treatment of new-onset pulmonary TB is very long, consisting of a six months therapy of four antibiotics (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months, and only rifampicin and isoniazid for the last four months). Current state of the art: To fight TB globally and more efficiently, it is essential to shorten the treatment for TB with new drugs that are efficient also against LTBI. To facilitate discovery of such drugs, in vitro models for LTBI can be used for high throughput screening of chemical libraries. Current in vitro models such as nutrient starvation (Betts et al. 2002), nutrient depletion (Hampshire et al. 2004; Rifat, Bishai, and Karakousis 2009), progressive hypoxia (Wayne and Hayes 1996), nitric oxide treatment (Martin I. Voskuil et al. 2003) and multiple stress (Deb et al. 2009) mimic the dormant state of Mtb, but the technical settings and equipment required for these models obstruct high throughput applications. Proposed model: The streptomycin (STR)-starved 18b model (SS18b) is a simple and drug discovery efficient Mtb latency model successfully applicable to both in vitro and in vivo settings (Zhang et al. 2012). It is based on the Mtb strain 18b, which is a STR-dependent mutant that enters a viable but nonreplicating state in the absence of STR (Hashimoto 1955). Despite the successful model, we know very little about 18b. How well does SS18b mimic the bacterial response to the complex host-pathogen interactions underlying LTBI, and how does the SS18b response compare to that of other dormancy models are still open questions. In this work we analyse the complete genome of 18b and describe the transcriptomic response of 18b to STR depletion.

Dataset Information

Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis.

Publications

Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis.

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