The ins and outs of RND efflux pumps in Escherichia coli

Abstract

Infectious diseases remain one of the principal causes of morbidity and mortality in the world. Relevant authorities including the WHO and CDC have expressed serious concern regarding the continued increase in the development of multidrug resistance among bacteria. They have also reaffirmed the urgent need for investment in the discovery and development of new antibiotics and therapeutic approaches to treat multidrug resistant (MDR) bacteria. The extensive use of antimicrobial compounds in diverse environments, including farming and healthcare, has been identified as one of the main causes for the emergence of MDR bacteria. Induced selective pressure has led bacteria to develop new strategies of defense against these chemicals. Bacteria can accomplish this by several mechanisms, including enzymatic inactivation of the target compound; decreased cell permeability; target protection and/or overproduction; altered target site/enzyme and increased efflux due to over-expression of efflux pumps. Efflux pumps can be specific for a single substrate or can confer resistance to multiple antimicrobials by facilitating the extrusion of a broad range of compounds including antibiotics, heavy metals, biocides and others, from the bacterial cell. To overcome antimicrobial resistance caused by active efflux, efforts are required to better understand the fundamentals of drug efflux mechanisms. There is also a need to elucidate how these mechanisms are regulated and how they respond upon exposure to antimicrobials. Understanding these will allow the development of combined therapies using efflux inhibitors together with antibiotics to act on Gram-negative bacteria, such as the emerging globally disseminated MDR pathogen Escherichia coli ST131 (O25:H4). This review will summarize the current knowledge on resistance-nodulation-cell division efflux mechanisms in E. coli, a bacteria responsible for community and hospital-acquired infections, as well as foodborne outbreaks worldwide.

Antimicrobial Resistance, Biofilm Formation, and Phylogenetic Grouping of Uropathogenic Escherichia coli Isolates in Egypt: The Role of Efflux Pump-Mediated Resistance

“…Efflux pump systems are classified into five families: the ATP binding cassette (ABC) superfamily, the major facilitator superfamily (MFS), the Multidrug and toxiccompound extrusion (MATE) family, the small multidrug resistance (SMR) family and the resistance nodulation division (RND) family (9). The AcrAB-TolC pump that belongs to the RND family is the main efflux pump in E. coli clinical isolates (10).…”

Benzoate- and Salicylate-Tolerant Strains of Escherichia coli K-12 Lose Antibiotic Resistance during Laboratory Evolution

“…Thus, aromatic acid-inducible drug resistance incurs high energy costs associated with expression of so many genes, as well as the energy consumption by efflux pumps (38). Given the high energy cost, bacteria face a trade-off between inducible drug resistance and the toxicity of the drugs (39).…”

Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase

“…Many antibiotics are transported out of gram-negative organisms by a bacterial efflux transporter in the resistance-nodulation-division (RND) protein family that spans the cell envelope 36,37 ; specifically the AcrAB-TolC tripartite pump is found in E. coli , Salmonella spp. , and Shigella spp .…”

“…, and Shigella spp . and contributes to multidrug resistance 37–39 . Our observation that 3–5 are most active against strains of the gram-negative bacteria E. coli , S. enterica , and S. flexneri— and very potent against strains harboring the Δ tolC mutation—supports the hypothesis that the cyano and trifluoromethyl modifications in the 3-position of the benzenesulfonamide ring reduce drug efflux against this family of drug pumps.…”