Efflux pump inhibitors for bacterial pathogens: From bench to bedside

Abstract

With the advent of antibiotics, bacterial infections were supposed to be a thing of past. However, this instead led to the selection and evolution of bacteria with mechanisms to counter the action of antibiotics. Antibiotic efflux is one of the major mechanisms, whereby bacteria pump out the antibiotics from their cellular interior to the external environment using special transporter proteins called efflux pumps. Inhibiting these pumps seems to be an attractive strategy at a time when novel antibiotic supplies are dwindling. Molecules capable of inhibiting these pumps, known as efflux pump inhibitors (EPIs), have been viewed as potential therapeutic agents that can rejuvenate the activity of antibiotics that are no longer effective against bacterial pathogens. EPIs follow some general mechanisms of efflux inhibition and are derived from various natural as well as synthetic sources. This review focuses on EPIs and identifies the challenges that have kept these futuristic therapeutics away from the commercial realm so far.

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

“…From a therapeutic perspective, utilizing a chemical combination in which one compound targets an essential process and the other disables a major resistance mechanism provides an attractive strategy that has been explored for both antimicrobial and cancer treatment 39 , 52 , 63 – 66 . In the case of efflux inhibitors, not only does this strategy enhance the efficacy of the other compound, but if applied early in the course of intervention, it can also reduce the rate at which resistance emerges 39 , 67 .…”

Biofilm Eradication by Symmetrical Selenoesters for Food-Borne Pathogens

“…In addition, Se-K1 was also interesting, as it showed a biofilm inhibiting effect higher than 50% against MRSA. It was surprising that Se-K2 promoted the biofilm formation of S. aureus MRSA, because it has the same chemical formula as Se-K1 (both are 2-oxopropyl selenodiesters); they only differ in the substitution pattern at the phenyl ring, such that Se-K1 has a para substitution (1,4) and Se-K2 has a meta substitution (1,3). It is interesting to see how such a small change in the substitution pattern at the core phenyl ring leads to completely different activities.…”

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

“…Efflux pumps are highly conserved structures in pro-and eukaryotes. Comprehensive reviews have summarized a plethora of data describing interactions of a broad variety of agents with efflux pumps [238][239][240][241][242][243][244]. In general, nonsteroidal anti-inflammatory drugs (NSAIDS) and acetylsalicylic acid (aspirin ® ), its major metabolite salicylic acid, and acetaminophen (paracetamol ® ) in particular, interact not only with efflux pumps but exert pleiotropic antibacterial activities against bacteria many of which are equivocal [245][246][247][248][249].…”