An Intertwined Network of Regulation Controls Membrane Permeability Including Drug Influx and Efflux in Enterobacteriaceae

Abstract

The transport of small molecules across membranes is a pivotal step for controlling the drug concentration into the bacterial cell and it efficiently contributes to the antibiotic susceptibility in Enterobacteriaceae. Two types of membrane transports, passive and active, usually represented by porins and efflux pumps, are involved in this process. Importantly, the expression of these transporters and channels are modulated by an armamentarium of tangled regulatory systems. Among them, Helix-turn-Helix (HTH) family regulators (including the AraC/XylS family) and the two-component systems (TCS) play a key role in bacterial adaptation to environmental stresses and can manage a decrease of porin expression associated with an increase of efflux transporters expression. In the present review, we highlight some recent genetic and functional studies that have substantially contributed to our better understanding of the sophisticated mechanisms controlling the transport of small solutes (antibiotics) across the membrane of Enterobacteriaceae. This information is discussed, taking into account the worrying context of clinical antibiotic resistance and fitness of bacterial pathogens. The localization and relevance of mutations identified in the respective regulation cascades in clinical resistant strains are discussed. The possible way to bypass the membrane/transport barriers is described in the perspective of developing new therapeutic targets to combat bacterial resistance.

Interplay between OmpA and RpoN Regulates Flagellar Synthesis in Stenotrophomonas maltophilia

“…Therefore, OmpA is an ideal target for inhibitor design. For Gram-negative bacteria, the double membranes may be a natural barrier for the entrance of foreign molecules [2,3]. Given that OmpA is the OMP of the greatest abundance in S. maltophilia, the accessibility of an OmpA inhibitor to OmpA can be highly efficient.…”

“…Gram-negative bacteria are surrounded by two membranes, which confine the periplasmic space containing the peptidoglycan [1]. This double membrane may be impenetrable to antibiotics, noxious agents, or other foreign compounds [2,3]. The outer membrane (OM) is a complex organelle that provides a barrier to protect bacteria from hazards in their environment.…”

Directed Recovery and Molecular Characterization of Antibiotic Resistance Plasmids from Cheese Bacteria

“…Increased MICs for some antibiotics have largely been attributed to non-specific mechanisms such as reduced antibiotic uptake, reduced cell permeability, the thickness and compactness of the cell wall, defective cell wall autolytic systems, and the presence of multidrug resistance transporters [65,66]. Although none of the proteins encoded by ORFs from pTC6.1-pTC6.2, or pTC7 could be assigned any of these functions, it cannot be ruled out that the moderate tetracycline resistance provided to L. casei and L. plantarum is associated with one or more of the above mechanisms.…”

Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria

“…Therefore, mutations in acrR result in the overexpression of AcrAB-TolC, leading to MDR phenotypes in E. coli and Salmonella isolates [ 119 , 120 ]. AcrR has also been identified as a repressor of other regulatory complexes, including MarAB and SoxS, as summarised by Ferrand and colleagues [ 121 ]. Mutations in another regulatory gene, mexR , have been shown to increase expression of the associated MexAB-OprM efflux system in P. aeruginosa isolates [ 122 ].…”

“…Mutations in another regulatory gene, mexR , have been shown to increase expression of the associated MexAB-OprM efflux system in P. aeruginosa isolates [ 122 ]. Other similar repressors, including RamR and OqxR, have also been linked to efflux pump regulation and overexpression, resulting in antimicrobial resistance for multiple species [ 121 ]. Environmental factors can also stimulate the overexpression of efflux pumps and can include oxidative stress, antibiotic application as well as the presence of specific ligands.…”