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.
Highlights
During the last decades, the antibiotic resistance of Gram-negative pathogens has become worrying due to the spreading of multidrug resistant strains that create clinical therapeutic outcomes [1,2,3]
It was expressed with higher levels in Enterobacter cloacae, Klebsiella aerogenes, and Salmonella Multi drug resistant (MDR) strains compared to MarA and was found to be more effective than MarA, RarA, SoxS for decreasing envelope permeability in Klebsiella [24,52,60]
We can mention the recent study of an isolate of Salmonella paratyphi A, resistant to macrolides, that exhibits mutations in numerous regulators conferring multi-drug resistances [129]
Summary
The antibiotic resistance of Gram-negative pathogens has become worrying due to the spreading of multidrug resistant strains that create clinical therapeutic outcomes [1,2,3]. The IM contains multidrug efflux pumps that actively expel toxic molecules and peptides from the bacterial cell [9] These two membranes form a well-designed permeability barrier that efficiently act to control the intracellular accumulation of antibiotics and represent a prominent factors promoting intrinsic resistance of Gram-negative bacteria to a broad range of antimicrobial agents [6,9,10,11]. The RND family contributes to the major membrane-associated mechanisms of efflux in Enterobacteriaceae and the more relevant complex described in clinical isolate belong to AcrAB-TolC system [16,17] Due to their role in the bacterial adaptation to external stresses, these passive and active transports are tightly regulated in Enterobacteriaceae.
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