Bacterial Efflux Pumps Involved in Multidrug Resistance and their Inhibitors: Rejuvinating the Antimicrobial Chemotherapy

Abstract

Active efflux of antibiotics is one of the major mechanisms of drug resistance in bacteria. The efflux process is mediated by membrane transporters with a large variety of unrelated compounds as their substrates. Though these pumps are responsible for the low intrinsic resistance of a bacterium to a drug, their overexpression, accumulation of mutations in these proteins and their synergy with other drug resistance mechanisms hampers effective antimicrobial treatment. As efflux pumps have been reported to play vital roles in mediating multidrug resistance in clinical isolates from varied geographic locations and varied populations, the inhibition of efflux pumps appears to be an attractive approach to combat the problem of drug resistance. Efflux pump inhibitors can be utilized for increasing the antibiotic concentration inside a pathogenic cell making these drugs more effective, reduce the accumulation of other resistance mechanisms in a cell and for diagnostic purposes to evaluate the presence and contribution of the efflux mechanism in a pathogen. A large number of inhibitors have been discovered and patented in last two decades but the process of discovery, testing and commercialization is rather slow. Some of the important inhibitors include the energy decouplers, phenothiazines, analogs of popular antibiotics, inhibitors of serotonin re-uptake, to name a few, that have been used as adjuvants in the antimicrobial chemotherapy to potentiate the activity of some important antimicrobials in deadly pathogens that have worried the mankind since long. This review describes the role of efflux pumps in governing the resistance phenotype of a pathogen, efflux pumps found in bacteria and the efflux pump inhibitors that have been studied and patented so far.

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

“…Many other types of compounds have been investigated as potential EPIs and reviewed (16,981,(985)(986)(987). Quinoline and pyridoquinoline derivatives were investigated as inhibitors of E. aerogenes AcrAB by the Pagès group (988).…”

Clinical Isolates of Vibrio cholerae O1 El Tor Ogawa of 2009 from Kolkata, India: Preponderance of SXT Element and Presence of Haitian ctxB Variant

“…In earlier studies from this laboratory, various genetic factors like efflux pumps, plasmids, integrons, qnr genes and mutations in topoisomerases were evaluated for their role in conferring antibiotic resistance [17]–[20]. In the present study, V. cholerae O1 Ogawa isolated from the patients of Infectious Diseases Hospital (IDH) of Kolkata, India, in 2009, were examined for genetic factors governing their antibiotic resistance profiles.…”

Challenges and future prospects of antibiotic therapy: from peptides to phages utilization

“…This is a very common resistance mechanism found in Escherichia coli, P. aeruginosa, Mycobacterium smegmatis, and Staphylococcus aureus (Takiff et al, 1996). Depending upon their varying structure and function, efflux pumps are subdivided into five classes: SMR pumps of the drug/metabolite transporters (DMTs) superfamily, ABC, RND, MFS, and MATE transporters of the multi-drug/oligosaccharidyl-lipid/polysaccharide flippases (MOP) superfamily (Piddock, 2006; Bhardwaj and Mohanty, 2012). …”