Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria

Abstract

Antibiotic resistance mechanisms reported in Gram-negative bacteria are producing a worldwide health problem. The continuous dissemination of «multi-drug resistant» (MDR) bacteria drastically reduces the efficacy of our antibiotic “arsenal” and consequently increases the frequency of therapeutic failure. In MDR bacteria, the over-expression of efflux pumps that expel structurally-unrelated drugs contributes to the reduced susceptibility by decreasing the intracellular concentration of antibiotics. During the last decade, several clinical data indicate an increasing involvement of efflux pumps in the emergence and dissemination of resistant Gram-negative bacteria. It is necessary to clearly define the molecular, functional and genetic bases of the efflux pump in order to understand the translocation of antibiotic molecules through the efflux transporter. The recent investigation on the efflux pump AcrB at its structural and physiological level, including the identification of drug affinity sites and kinetic parameters for various antibiotics, may open the way to rationally develop an improved new generation of antibacterial agents as well as efflux inhibitors in order to efficiently combat efflux-based resistance mechanisms.

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

“…2B). Beyond activity at the target level, compound 1 was shown to have MICs against both Gram-positive (e.g., Staphylococcus aureus and Streptococcus pneumoniae) and Gram-negative (e.g., E. coli and Pseudomonas aeruginosa) bacterial pathogens, with significantly greater activity against strains in which genes for major efflux systems (22) had been inactivated (Table 1). To further evaluate the mechanism of action of compound 1, we monitored the incorporation of radiolabeled, pathway-specific precursors (23) in an efflux-deficient strain of E. coli.…”

The crystal structure of multidrug-resistance regulator RamR with multiple drugs

“…The important role of drug efflux systems in multidrug resistance has been well documented in eukaryotes as well as in prokaryotes 1,2 . Gram-negative bacteria are often intrinsically resistant to a number of antimicrobial agents, and multidrug transporters of the resistance-nodulationcell division family such as AcrAB are particularly effective in generating this resistance 3 .…”

Anti-virulence Strategies to Target Bacterial Infections

“…With the added advantage that uptake of antibiotics into Gram-negative bacteria is slowed down by decreased permeability of the bacterial outer membrane, the bacteria are less susceptible to efflux pump substrates even those with poor affinity, as the rate of efflux usually exceeds that of influx (Nikaido and Pages 2012). Discovering compounds that selectively inhibit the bacterial efflux pumps may lead to the development of therapies that could restore sensitivity to antibiotics.…”

“…They transport a variety of toxic substances from the bacterial cell, including antibiotics such as fluoroquinolones, β-lactams, tetracyclines, and oxazolidines, mediating intrinsic resistance of the bacteria to these substances (Piddock et al 2006;Nikaido and Pages 2012). Phenylalanyl arginyl β-naphthylamide (PAβN) was discovered in a high-throughput screen for molecules that sensitize efflux pump-overexpressing P. aeruginosa to levofloxacin (Renau et al 1999).…”