Clinical implications of multiple drug resistance efflux pumps of pathogenic bacteria

Resistance of microorganisms to many classes of antibiotics and other drugs is a major problem throughout the world. This antimicrobial resistance can be mediated by various mechanisms such as enzymatic inactivation of the drug, alteration of the target and decreased intracellular concentration of the antimicrobial. The latter mechanism is mediated by either decreased influx or increased efflux or a combination of both. Recently, efflux has become increasingly recognized as a major component of resistance. Some efflux pumps selectively extrude specific antibiotics such as macrolides, lincosamides and/or streptogramins and tetracyclines, whereas others, referred to as multiple drug resistance pumps, expel a variety of structurally diverse anti-infectives with different modes of action. This phenomenon, whereby a single transporter is able to recognize and transport multiple antimicrobials with no common structural homology, was first described in the late 1980s in higher eukaryotes where P-glycoprotein was found to play a role in resistance to anti-cancer chemotherapeutic agents. Later, it became apparent that efflux systems were also present in microorganisms. Efflux pump inhibitors offer considerable promise as therapeutic agents, as they should restore the activity of standard antibiotics.