Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily

Abstract

Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS) is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS.

Modulation of the multidrug efflux pump EmrD-3 from Vibrio cholerae by Allium sativum extract and the bioactive agent allyl sulfide plus synergistic enhancement of antimicrobial susceptibility by A. sativum extract

“…1), as reported previously (Smith et al 2009). Addition of the energy uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), a known dissipater of the proton motive force (Kumar et al 2013a), at 360 s into the efflux assay shows deflection of the ethidium bromide fluorescence in cells with and without EmrD-3, demonstrating that the transport assay conditions were driven by a proton motive force prior to the addition of CCCP (Fig. 1).…”

“…Antimicrobial efflux pumps are known to be circumvented in the following ways: (a) inhibition of antimicrobial agent transport through the membrane, (b) inhibition of the interactions between subunits of tripartite efflux pumps, (c) inhibition of the energy modes that drive antimicrobial efflux, and (d) inhibition of efflux pump expression systems (Kumar and Schweizer 2005;Lewis 2001; Lomovskaya and Watkins 2001a, b). Inhibition of bacterial antimicrobial efflux pumps may improve the efficacy of clinically relevant antibiotics by increasing drug susceptibility and, thus, reducing the selection of antibiotic-resistant variants (Blair et al 2014;Kumar et al 2013a;Opperman and Nguyen 2015;Pages and Amaral 2009).…”

“…Efflux pump inhibitors have been studied for the EmrB (Barrero et al 2014), LmrP (Putman et al 1999, QacA (Dymek et al 2012), and the NorA (Schindler et al 2013) multidrug efflux pumps of the MFS superfamily, summarized recently (Andersen et al 2015;Kumar et al 2016;Mukherjee et al 2016). Due to their ubiquity in bacterial pathogens and their inherent nature to circumvent infectious disease therapies, multidrug efflux pumps of the MFS are postulated to be suitable targets for modulation (Kumar et al 2013aMukherjee et al 2016). Few studies have been reported regarding the modulation of multidrug efflux pumps from V. cholerae, and such resistance determinants would make good modulation targets (Mukherjee et al 2016;Varela et al 2013).…”

“…EmrD-3 confers resistance to multiple structurally diverse antimicrobial agents like chloramphenicol, erythromycin, linezolid, minocycline, rhodamine 6G, rifampin, tetraphenylphosphonium chloride, and trimethoprim (Smith et al 2009). Modulation of bacterial multidrug efflux pumps like EmrD-3 may circumvent antimicrobial resistance and diminish the conditions that foster movement and dissemination of bacterial pathogens to other populations (Kumar et al 2013a;Mukherjee et al 2016).…”

Prevalence of AmpC β-lactamase among Gram-negative bacteria recovered from clinical specimens in Benin City, Nigeria

“…Drug and multidrug resistant bacterial pathogens that are causative agents of infectious disease constitute a serious public health concern [1]. The development of new antibiotics has been accompanied by the steady increase of antibiotic-resistant bacterial strains and the diversity of mechanisms used by bacteria to surpass the lethal effect of these compounds [2].…”