Inhibiting Bacterial Drug Efflux Pumps via Phyto-Therapeutics to Combat Threatening Antimicrobial Resistance

Abstract

Antibiotics, once considered the lifeline for treating bacterial infections, are under threat due to the emergence of threatening antimicrobial resistance (AMR). These drug-resistant microbes (or superbugs) are non-responsive to most of the commonly used antibiotics leaving us with few treatment options and escalating mortality-rates and treatment costs. The problem is further aggravated by the drying-pipeline of new and potent antibiotics effective particularly against the drug-resistant strains. Multidrug efflux pumps (EPs) are established as principal determinants of AMR, extruding multiple antibiotics out of the cell, mostly in non-specific manner and have therefore emerged as potent drug-targets for combating AMR. Plants being the reservoir of bioactive compounds can serve as a source of potent EP inhibitors (EPIs). The phyto-therapeutics with noteworthy drug-resistance-reversal or re-sensitizing activities may prove significant for reviving the otherwise fading antibiotics arsenal and making this combination-therapy effective. Contemporary attempts to potentiate the antibiotics with plant extracts and pure phytomolecules have gained momentum though with relatively less success against Gram-negative bacteria. Plant-based EPIs hold promise as potent drug-leads to combat the EPI-mediated AMR. This review presents an account of major bacterial multidrug EPs, their roles in imparting AMR, effective strategies for inhibiting drug EPs with phytomolecules, and current account of research on developing novel and potent plant-based EPIs for reversing their AMR characteristics. Recent developments including emergence of in silico tools, major success stories, challenges and future prospects are also discussed.

Quorum-Sensing Regulation of Antimicrobial Resistance in Bacteria

“…For example, the super resistant bacterium Staphylococcus aureus can specifically degrade penicillin by producing β-lactamase, and on the other hand, it can deprive methicillin of its ability to bind cell wall mucin synthase by producing PBP2a protein [27]. In another super bacterium Pseudomonas aeruginosa, in addition to being able to produce different drug efflux pumps to resist multiple types of antibiotics [28,29], resistance genes can also be obtained through horizontal gene transfer [30,31], and its bacteria changes in body shape and dense biofilms can resist almost all antibiotics on the market [32,33]. In recent years, researchers have found that the formation of bacterial biofilm resistance to bacteria is particularly important.…”

Tackling Antibiotic Resistance with Compounds of Natural Origin: A Comprehensive Review

“…This effect is mainly attributed to the inhibitory capacity of EPs of the phytochemicals present in the extract [ 172 ]. The activity of these plant molecules as inhibitors of microbial efflux pumps can act as restorers of antimicrobial susceptibility and open the door to combined antibiotic treatments, since these could exert their action more easily by not being expelled from the bacterial interior, allowing relive obsolete or discarded therapies due to this resistance mechanism [ 173 ]. A catechin, (-)-epigallocatechin gallate (EGCg), has shown sensitizing activity in S. aureus against tetracycline by inhibiting EPs such as Tet (K), increasing intracellular retention of the antibiotic and enhancing its effect [ 174 ].…”

PLGA microsphere-based composite hydrogel for dual delivery of ciprofloxacin and ginsenoside Rh2 to treat Staphylococcus aureus -induced skin infections

“…In S. aureus, several multidrug efflux pumps, such as NorA, NorB and MepA, have been described that are associated with resistance to antibiotics, and NorA is the most important and well characterized efflux pump (Holler et al 2012;Astolfi et al, 2017;Felicetti et al, 2017;Felicetti et al, 2018). It is reported that the stable hydrogen bonding interactions between ginsenoside Rh2 (G-Rh2) and Gln51/Asn340/ Ser226 residues at active binding site in the central cavity of protein was responsible for the inhibition of NorA pump, thus G-Rh2 could be used as an inhibitor of the NorA efflux pump to restore susceptibility to common antibiotics in multiple drug resistant (MDR) bacteria (Zhang et al, 2014;Shriram et al, 2018;Kumar et al, 2020). Meanwhile, G-Rh2 is one of the active compounds extracted from ginseng, exhibiting unique immune enhancement effect different from other efflux pump inhibitors (Lee et al, 2018).…”