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.
Highlights
The ins and outs of resistance-nodulation-cell division (RND) efflux pumps in Escherichia coliUCD Centre for Food Safety, School of Public Health, Physiotherapy and Population Science, UCD Centre for Molecular Innovation and Drug Discovery, University College Dublin, Dublin, Ireland
Escherichia coli is a well-recognized human pathogen
Resistance can occur due to: (i) accumulation of mutations involved in specific antimicrobial targets (e.g., mutations in quinolone resistance-determining regions (QRDRs) in gyrA, gyrB, parE, and parC genes) (Moon et al, 2010); (ii) antimicrobial inactivation/modification; (iii) acquisition of mobile genetic elements such as plasmids, transposons, or integrons acquired by horizontal gene transfer (HGT) (Carraro et al, 2014; Gillings, 2014); (iv) alteration in the cell wall composition; (v) reduced expression of cell wall porins, resulting in decreased influx of antimicrobials (Masi and Pagès, 2013); and (vi) over-expression of efflux pumps (Wang et al, 2001)
Summary
UCD Centre for Food Safety, School of Public Health, Physiotherapy and Population Science, UCD Centre for Molecular Innovation and Drug Discovery, University College Dublin, Dublin, Ireland. 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 reaffirmed the urgent need for investment in the discovery and development of new antibiotics and therapeutic approaches to treat multidrug resistant (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. There is 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).
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