Dataset Information

Mycobacterial Mutagenesis and Drug Resistance Are Controlled by Phosphorylation- and Cardiolipin-Mediated Inhibition of the RecA Coprotease.

ABSTRACT: Infection with Mycobacterium tuberculosis continues to cause substantial human mortality, in part because of the emergence of antimicrobial resistance. Antimicrobial resistance in tuberculosis is solely the result of chromosomal mutations that modify drug activators or targets, yet the mechanisms controlling the mycobacterial DNA-damage response (DDR) remain incompletely defined. Here, we identify RecA serine 207 as a multifunctional signaling hub that controls the DDR in mycobacteria. RecA S207 is phosphorylated after DNA damage, which suppresses the emergence of antibiotic resistance by selectively inhibiting the LexA coprotease function of RecA without affecting its ATPase or strand exchange functions. Additionally, RecA associates with the cytoplasmic membrane during the mycobacterial DDR, where cardiolipin can specifically inhibit the LexA coprotease function of unmodified, but not S207 phosphorylated, RecA. These findings reveal that RecA S207 controls mutagenesis and antibiotic resistance in mycobacteria through phosphorylation and cardiolipin-mediated inhibition of RecA coprotease function.

SUBMITTER: Wipperman MF

PROVIDER: S-EPMC6389330 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Mycobacterial Mutagenesis and Drug Resistance Are Controlled by Phosphorylation- and Cardiolipin-Mediated Inhibition of the RecA Coprotease.

Wipperman Matthew F MF Heaton Brook E BE Nautiyal Astha A Adefisayo Oyindamola O Evans Henry H Gupta Richa R van Ditmarsch Dave D Soni Rajesh R Hendrickson Ron R Johnson Jeff J Krogan Nevan N Glickman Michael S MS

Molecular cell 20180830 1

Infection with Mycobacterium tuberculosis continues to cause substantial human mortality, in part because of the emergence of antimicrobial resistance. Antimicrobial resistance in tuberculosis is solely the result of chromosomal mutations that modify drug activators or targets, yet the mechanisms controlling the mycobacterial DNA-damage response (DDR) remain incompletely defined. Here, we identify RecA serine 207 as a multifunctional signaling hub that controls the DDR in mycobacteria. RecA S207 ...[more]

PMID: 30174294

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Project description:Mycobacteriosis is mainly caused by two groups of species: Mycobacterium tuberculosis and non-tuberculosis mycobacteria (NTM). The pathogens cause not only respiratory infections, but also general diseases. The common problem in these pathogens as of today is drug resistance. Tuberculosis (TB) is a major public health concern. A major challenge in the treatment of TB is anti-mycobacterial drug resistance (AMR), including multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Recently, the success rate of the treatment of drug-resistant tuberculosis (DR-TB) has improved significantly with the introduction of new and repurposed drugs, especially in industrialized countries such as Japan. However, long-term treatment and the adverse events associated with the treatment of DR-TB are still problematic. To solve these problems, optimal treatment regimens designed/tailor-made for each patient are necessary, regardless of the location in the world. In contrast to TB, NTM infections are environmentally oriented. Mycobacterium avium-intracellulare complex (MAC) and Mycobacterium abscessus species (MABS) are the major causes of NTM infections in Japan. These bacteria are naturally resistant to a wide variation of antimicrobial agents. Macrolides, represented by clarithromycin (CLR) and amikacin (AMK), show relatively good correlation with treatment success. However, the efficacies of potential drugs for the treatment of macrolide-resistant MAC and MABS are currently under evaluation. Thus, it is particularly difficult to construct an effective treatment regimen for macrolide-resistant MAC and MABS. AMR in NTM infections are rather serious in Japan, even when compared with challenges associated with DR-TB. Given the AMR problems in TB and NTM, the appropriate use of drugs based on accurate drug susceptibility testing and the development of new compounds/regimens that are strongly bactericidal in a short-time course will be highly expected.

Dataset Information

Mycobacterial Mutagenesis and Drug Resistance Are Controlled by Phosphorylation- and Cardiolipin-Mediated Inhibition of the RecA Coprotease.

Publications

Mycobacterial Mutagenesis and Drug Resistance Are Controlled by Phosphorylation- and Cardiolipin-Mediated Inhibition of the RecA Coprotease.

Similar Datasets

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