Efflux, Signaling and Warfare in a Polymicrobial World

Abstract

The discovery void of antimicrobial development has occurred at a time when the world has seen a rapid emergence and spread of antimicrobial resistance, the 'perfect storm' as it has often been described. While the discovery and development of new antibiotics has continued in the research sphere, the pipeline to clinic has largely been fed by derivatives of existing classes of antibiotics, each prone to pre-existing resistance mechanisms. A novel approach to infection management has come from the ecological perspective whereby microbial networks and evolved communities already possess small molecular capabilities for pathogen control. The spatiotemporal nature of microbial interactions is such that mutualism and parasitism are often two ends of the same stick. Small molecule efflux inhibitors can directly target antibiotic efflux, a primary resistance mechanism adopted by many species of bacteria and fungi. However, a much broader anti-infective capability resides within the action of these inhibitors, borne from the role of efflux in key physiological and virulence processes, including biofilm formation, toxin efflux, and stress management. Understanding how these behaviors manifest within complex polymicrobial communities is key to unlocking the full potential of the advanced repertoires of efflux inhibitors.

Keywords: antimicrobial resistance; biofilms; efflux; effluxome; microbiome; polymicrobial infections; symbiosis.

Figure 1

(A) Efflux in monoculture has been studied extensively, with a broad spectrum of systems for which substrates have been profiled and characterized. Perhaps the best studied of these have been antibiotics in the context of AMR mediated through efflux of specific classes of intracellular targeting drugs. (B) Efflux in a polymicrobial context. (i) Host signaling and interspecies/interkingdom communication systems in bacteria, yeast, and fungi, create a complex networked environment where efflux systems and their inhibitors can have a significant input into the dynamic outcomes of intervention. Furthermore, affinities of EPI’s for efflux pumps may vary at the species level, with potential for off-species effects targeting as yet uncharacterized community members, thus insulating the intended target from the full dose of the intervention. (ii) Inhibiting the metabolic role of efflux systems in expulsion of metabolites and scavenging factors such as siderophores could have important consequences within polymicrobial communities where, e.g., iron acquisition by siderophore non-producers is affected through inhibition of symbiotic partners. (iii) The cross-protection afforded to some species of bacteria can also be lost through efflux inhibition whereby, e.g., protection arising from recognition of indole efflux by Escherichia coli is lost to Pseudomonas putida. Created using Biorender.com.