Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

Abstract

SUMMARY 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.

In vitro selection of fluoroquinolone resistance in Brucella melitensis

“…Sequencing NorMI and NorMII genes in two mutants did not reveal any mutation. However, overexpression of efflux pumps is usually related to mutation in local or global regulator genes and less frequently in structural genes [33]. The former genes are currently uncharacterised in B. melitensis.…”

“…MATE family efflux pumps have been described in Vibrio parahaemolyticus, Pseudomonas aeruginosa, Campylobacter spp. and Bacteroides thetaiotaomicron [33]. Two putative MATE family efflux pumps have been recently described in B. melitensis, i.e.…”

“…An alanine residue at codon position 83 is found naturally in Mycobacterium tuberculosis [28], B. abortus [25] and B. melitensis, which display intermediate-level resistance to ciprofloxacin and ofloxacin. Finally, Ala83Val substitution has been reported in M. tuberculosis [29], B. abortus [25] PAN is known to inhibit efflux pumps of the MATE family in different Gram-negative bacterial species [33]. It is a dipeptide amide that acts as an EPI by competing with the fluoroquinolone compounds, thus precluding extrusion of these antibiotics.…”

Caracterização molecular da resistência aos carbapenêmicos em enterobactérias isoladas em hospitais brasileiros

“…As bombas de efluxo, associadas à resistência aos antimicrobianos de importância clínica, geralmente pertencem às famílias RND (resistence-nodulation division) e MFS (major facilitator superfamily) (Piddock, 2006, Davin-Regli et al, 2008. Este mecanismo de efluxo contribui para a resistência intrínseca e adquirida em Enterobactérias.…”

“…(Piddock, 2006). Em P. aeruginosa, o sistema Mex tem sido descrito como mecanismo de resistência a diversos antimicrobianos, entre eles, ao meropenem.…”