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Vitamin C Stimulon in Mycobacterium tuberculosis

ABSTRACT: The emergence of drug resistance among tuberculosis (TB) patients is often associated with their non-compliance to the length of the chemotherapy, which can reach up to 2 years for the treatment of multi-drug-resistant (MDR) TB. Drugs that would kill TB faster and would not lead to the development of drug resistance could shorten chemotherapy significantly. In Escherichia coli, the common mechanism of cell death by bactericidal antibiotics is the generation of highly reactive hydroxyl radicals via the Fenton reaction. Since ascorbic acid (vitamin C) is known to drive the Fenton reaction, we tested whether the Fenton reaction could lead to a bactericidal event in Mycobacterium tuberculosis by treating M. tuberculosis cultures with vitamin C. Here, we report that the addition of vitamin C to drug-susceptible, MDR and extensively drug-resistant (XDR) M. tuberculosis strains results in sterilization of the cultures in vitro. We show that the sterilizing effect of vitamin C on M. tuberculosis was dependent on the production of high ferrous ion levels and reactive oxygen species. Although, this potent sterilizing activity of vitamin C against M. tuberculosis in vitro was not observed in mice, we believe this activity needs further investigation.

ORGANISM(S): Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv

PROVIDER: GSE42293 | GEO | 2013/05/24

SECONDARY ACCESSION(S): PRJNA181017

REPOSITORIES: GEO

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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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Vitamin C Stimulon in Mycobacterium tuberculosis

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