title: Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm.
abstract: The intrinsic resistance of Mycobacterium tuberculosis and related pathogens to most common antibiotics limits chemotherapeutic options to treat tuberculosis and other mycobacterial diseases. Resistance has traditionally been attributed to the unusual multi-layer cell envelope that functions as an effective barrier to the penetration of antibiotics. Recent insights into mechanisms that neutralize the toxicity of antibiotics in the cytoplasm have revealed systems that function in synergy with the permeability barrier to provide intrinsic resistance. Here, we highlight the growing pool of information about internal, antibiotic-responsive regulatory proteins and corresponding resistance genes, and present new concepts that rationalize how they might have evolved. Pharmaceutical inhibition of these intrinsic systems could make many previously available antibiotics active against M. tuberculosis.
authors.affiliation: Department of Microbiology and Immunology, Life Sciences Centre, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. liemn@interchange.ubc.ca
authors.forename: Liem
authors.initials: L
authors.lastname: Nguyen
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Thompson
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D002473:Cell Wall / Q000502:physiology / Q000648:ultrastructure; D003545:Cysteine; D004187:Disaccharides / Q000378:metabolism / Q000502:physiology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics / Q000502:physiology*; D006020:Glycopeptides; D007294:Inositol; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D009161:Mycobacterium / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D018272:Porins / Q000235:genetics / Q000502:physiology; D011720:Pyrazoles / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004187:Disaccharides; D006020:Glycopeptides; D026901:Membrane Transport Proteins; D018272:Porins; D011720:Pyrazoles; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; C089265:mycothiol; D007294:Inositol; D003545:Cysteine