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Chemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis.

TitleChemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsXu W, DeJesus MA, Rücker N, Engelhart CA, Wright MG, Healy C, Lin K, Wang R, Park SWoong, Ioerger TR, Schnappinger D, Ehrt S
JournalAntimicrob Agents Chemother
Volume61
Issue12
Date Published2017 12
ISSN1098-6596
KeywordsAdenosine Triphosphatases, Antitubercular Agents, Bacterial Proteins, Cell Wall, Drug Resistance, Multiple, Bacterial, Ethambutol, Galactans, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Humans, Ion Pumps, Isoniazid, Ligases, Mannosyltransferases, Membrane Transport Proteins, Meropenem, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Mycolic Acids, Peptidoglycan, Rifampin, Serine Proteases, Thienamycins, Vancomycin
Abstract

Chemotherapy for tuberculosis (TB) is lengthy and could benefit from synergistic adjuvant therapeutics that enhance current and novel drug regimens. To identify genetic determinants of intrinsic antibiotic susceptibility in , we applied a chemical genetic interaction (CGI) profiling approach. We screened a saturated transposon mutant library and identified mutants that exhibit altered fitness in the presence of partially inhibitory concentrations of rifampin, ethambutol, isoniazid, vancomycin, and meropenem, antibiotics with diverse mechanisms of action. This screen identified the cell envelope to be a major determinant of antibiotic susceptibility but did not yield mutants whose increase in susceptibility was due to transposon insertions in genes encoding efflux pumps. Intrinsic antibiotic resistance determinants affecting resistance to multiple antibiotics included the peptidoglycan-arabinogalactan ligase Lcp1, the mycolic acid synthase MmaA4, the protein translocase SecA2, the mannosyltransferase PimE, the cell envelope-associated protease CaeA/Hip1, and FecB, a putative iron dicitrate-binding protein. Characterization of a deletion mutant confirmed FecB to be involved in the intrinsic resistance to every antibiotic analyzed. In contrast to its predicted function, FecB was dispensable for growth in low-iron medium and instead functioned as a critical mediator of envelope integrity.

DOI10.1128/AAC.01334-17
Alternate JournalAntimicrob Agents Chemother
PubMed ID28893793
PubMed Central IDPMC5700314
Grant ListU19 AI107774 / AI / NIAID NIH HHS / United States
U19 AI111143 / AI / NIAID NIH HHS / United States

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