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.

The Art of War with Pseudomonas aeruginosa: Targeting Mex Efflux Pumps Directly to Strategically Enhance Antipseudomonal Drug Efficacy

“…RND pumps not only drive the efflux of intrinsic toxic metabolites, safeguarding the bacterial milieu from their detrimental effects [ 65 , 66 ], but also play a role in modulating quorum sensing [ 67 , 68 ], influencing biofilm formation [ 69 ] and impacting bacterial virulence [ 70 , 71 ]. Thus, these versatile pumps contribute to fundamental cellular defense mechanisms [ 71 , 72 ]. Moreover, these proteins transport a specific range of antimicrobials.…”

Nanosilver: An Old Antibacterial Agent with Great Promise in the Fight against Antibiotic Resistance

“…All pumps are in the cytoplasmic membrane but can differ in their energy source (proton motive force/ATP), substrate specificity, and/or structure [ 225 ]. Regarding antibiotic resistance, the six most described efflux pump types include the major facilitator superfamily, the small-MDR-resistance family, the proteobacterial antimicrobial compound efflux family, the multidrug and toxic compound extrusion family, the ATP-binding cassette superfamily, and the resistance nodulation division family (RND) [ 225 , 226 ]. Many environmental bacterial strains contain more than one type of efflux pump in their membranes, and the pump itself may be able to transport a variety of antibiotics out of the cell [ 225 , 226 ].…”

“…Regarding antibiotic resistance, the six most described efflux pump types include the major facilitator superfamily, the small-MDR-resistance family, the proteobacterial antimicrobial compound efflux family, the multidrug and toxic compound extrusion family, the ATP-binding cassette superfamily, and the resistance nodulation division family (RND) [ 225 , 226 ]. Many environmental bacterial strains contain more than one type of efflux pump in their membranes, and the pump itself may be able to transport a variety of antibiotics out of the cell [ 225 , 226 ]. Pathogenic bacteria may also possess several types of efflux pumps, in addition to overexpressing them [ 227 ].…”