1. Mycobacterial Mutagenesis and Drug Resistance Are Controlled by Phosphorylation- and Cardiolipin-Mediated Inhibition of the RecA Coprotease
- Author
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Wipperman, Matthew F, Heaton, Brook E, Nautiyal, Astha, Adefisayo, Oyindamola, Evans, Henry, Gupta, Richa, van Ditmarsch, Dave, Soni, Rajesh, Hendrickson, Ron, Johnson, Jeff, Krogan, Nevan, and Glickman, Michael S
- Subjects
Biochemistry and Cell Biology ,Medical Microbiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Biodefense ,Genetics ,Rare Diseases ,Antimicrobial Resistance ,Infectious Diseases ,Tuberculosis ,Emerging Infectious Diseases ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,Adenosine Triphosphatases ,Cardiolipins ,DNA Damage ,Drug Resistance ,Bacterial ,Humans ,Mutagenesis ,Mycobacterium tuberculosis ,Phosphorylation ,Rec A Recombinases ,Serine ,DNA repair ,SOS response ,antibiotic response ,tuberculosis ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - 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.
- Published
- 2018