Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria.
Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed.
Piddock
Laura J V
LJ
Antimicrobial Agents Research Group, Division of Immunity and Infection, The Medical School, University of Birmingham, Birmingham, United Kingdom, B15 2TT. l.j.v.piddock@bham.ac.uk
D000470:Alkaloids / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002876:Chromosomes, Bacterial / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics; D004202:Disinfectants / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D005809:Genes, Regulator; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009154:Mutation; D011401:Promoter Regions, Genetic; D014774:Virulence
D000470:Alkaloids; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D004251:DNA Transposable Elements; D004202:Disinfectants; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins