Transporters, physiology, efflux inhibition and the challenge of clinical implementation

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About this Research Topic

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Background

One major contributor of resistance to many classes of chemotherapeutic and antimicrobial agents is multidrug efflux systems. Efflux occurs due to the activity of membrane transport systems which also perform essential roles in cellular metabolism-physiology and exhibit activity in a wide range of organisms. Based on their sequence similarity and structural homology, efflux systems are classified into six super-families: ATP-binding cassettes (ABC), major facilitators (MFS), resistance-nodulation cell division (RNDs), small multidrug resistance family (SMR), multi-antimicrobial extrusion protein family (MATE), and multidrug endosomal transporters (MET). The first five families are found in microorganisms while the MET family appears restricted to higher eukaryotes. Representatives of all groups are expressed in mammalian cells. They differ in membrane topology, energy coupling mechanisms, and most importantly in substrate specificity.
Inhibition of multidrug efflux systems has been a fundamental therapeutic challenge both in cancer and infectious diseases. There are three generations of inhibitors in mammalian systems with moderate success in the clinic and virtually no evidence for successful clinical validation of efflux inhibitors in prokaryotes. The deployment and complementation of strategies involving the use for small molecule efflux inhibitors has been an active and rapidly expanding research discipline. Advances in understanding cell physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. This core information is a stepping stone in the challenge of highlighting an effective drug development path for efflux inhibition since the puzzle of clinical implementation remains unsolved. This Research Topic emphasizes in the description of a variery of efflux systems, summarizes current trends in the discovery of inhibitors, highligths distinct and overlapping roles of efflux systems in cell physiology, attempts to identify a translational path and discusses potential avenues for pharmacological inhibitor implementation and development. The restoration of antimicrobial and chemotherapeutic efficacy is definitely appealing but is not yet at a therapeutic stage. The challenge for the proposed topic is to underline the conceptual and methodological gaps barring clinical implementation for efflux inhibition.

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