title: Inhibition of drug efflux in mycobacteria with phenothiazines and other putative efflux inhibitors.
abstract: Mycobacteria are responsible for some of the oldest diseases known to man, usually associated with high morbility and mortality rates. An example is tuberculosis (TB), a major public health problem that accounts for eight million new cases each year. Furthermore, the increase of multidrug and extremely-drug resistance seriously threatens the success of the TB control programmes. Resistance to anti-mycobacterial drugs is often due to spontaneous mutations in target genes, followed by selection of resistant mutants during treatment. However, this does not explain all cases of drug resistance and other mechanism(s) may be involved, namely efflux pumps that extrude the drug to the exterior of the cell. Efflux pumps are becoming attractive drug targets for the development of new anti-mycobacterial compounds and several efflux inhibitors have been developed and published in patent applications (i.e., WO2004062674, US2004204378, US2003118541, WO2008141012, WO2009110002, WO2010054102). However, none of these inhibitors is used in clinical practice. This review will focus on the potential use of efflux inhibitors as adjuvants of the anti-mycobacterial therapy, an approach that may restore the activity of antibiotics that are subject to efflux and render the mycobacteria more susceptible to drugs transported by these pumps.
authors.affiliation: Grupo de Micobactérias, Unidade de Microbiologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Rodrigues
authors.forename: José A
authors.initials: JA
authors.lastname: Aínsa
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D010640:Phenothiazines / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D010640:Phenothiazines