title: Antimicrobial efflux pumps and Mycobacterium tuberculosis drug tolerance: evolutionary considerations.
abstract: The need for lengthy treatment to cure tuberculosis stems from phenotypic drug resistance, also known as drug tolerance, which has been previously attributed to slowed bacterial growth in vivo. We discuss recent findings that challenge this model and instead implicate macrophage-induced mycobacterial efflux pumps in antimicrobial tolerance. Although mycobacterial efflux pumps may have originally served to protect against environmental toxins, in the pathogenic mycobacteria, they appear to have been repurposed for intracellular growth. In this light, we discuss the potential of efflux pump inhibitors such as verapamil to shorten tuberculosis treatment by their dual inhibition of tolerance and growth.
authors.affiliation: Department of Medicine (Division of Infectious Diseases), University of Washington, Seattle, WA, USA, jszumows@uw.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Szumowski
authors.forename: Kristin N
authors.initials: KN
authors.lastname: Adams
authors.forename: Paul H
authors.initials: PH
authors.lastname: Edelstein
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000494:pharmacology*; D001692:Biological Transport; D002121:Calcium Channel Blockers / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D019143:Evolution, Molecular; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology; D014700:Verapamil / Q000494:pharmacology*; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000995:Antitubercular Agents; D002121:Calcium Channel Blockers; D037521:Virulence Factors; D014700:Verapamil