title: Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations.
abstract: Multidrug resistance (MDR) refers to the capability of bacterial pathogens to withstand lethal doses of structurally diverse drugs which are capable of eradicating non-resistant strains. MDR has been identified as a major threat to the public health of human being by the World Health Organization (WHO). Among the four general mechanisms that cause antibiotic resistance including target alteration, drug inactivation, decreased permeability and increased efflux, drug extrusion by the multidrug efflux pumps serves as an important mechanism of MDR. Efflux pumps not only can expel a broad range of antibiotics owing to their poly-substrate specificity, but also drive the acquisition of additional resistance mechanisms by lowering intracellular antibiotic concentration and promoting mutation accumulation. Over-expression of multidrug efflux pumps have been increasingly found to be associated with clinically relevant drug resistance. On the other hand, accumulating evidence has suggested that efflux pumps also have physiological functions in bacteria and their expression is subject tight regulation in response to various of environmental and physiological signals. A comprehensive understanding of the mechanisms of drug extrusion, and regulation and physiological functions of efflux pumps is essential for the development of anti-resistance interventions. In this review, we summarize the development of these research areas in the recent decades and present the pharmacological exploitation of efflux pump inhibitors as a promising anti-drug resistance intervention.
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Sun
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Deng
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region. Electronic address: ayan8@hku.hk.
authors.forename: Aixin
authors.initials: A
authors.lastname: Yan
mesh_terms: D000818:Animals; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000254:growth & development; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D005798:Genes, Bacterial; D019450:Genes, MDR; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D014774:Virulence / Q000235:genetics / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins
keywords: Antibiotics; Efflux pump inhibitors; Multidrug efflux pumps; Multidrug resistance; Physiology; Regulation