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Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS).

ABSTRACT: The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters. MFS transporters are responsible for transporting a broad spectrum of substrates, either down their concentration gradient or uphill using the energy stored in the electrochemical gradients. Over the last 10 years, more than a hundred different MFS transporter structures covering close to 40 members have provided an atomic framework for piecing together the molecular basis of their transport cycles. Here, we summarize the remarkable promiscuity of MFS members in terms of substrate recognition and proton coupling as well as the intricate gating mechanisms undergone in achieving substrate translocation. We outline studies that show how residues far from the substrate binding site can be just as important for fine-tuning substrate recognition and specificity as those residues directly coordinating the substrate, and how a number of MFS transporters have evolved to form unique complexes with chaperone and signaling functions. Through a deeper mechanistic description of glucose (GLUT) transporters and multidrug resistance (MDR) antiporters, we outline novel refinements to the rocker-switch alternating-access model, such as a latch mechanism for proton-coupled monosaccharide transport. We emphasize that a full understanding of transport requires an elucidation of MFS transporter dynamics, energy landscapes, and the determination of how rate transitions are modulated by lipids.

SUBMITTER: Drew D

PROVIDER: S-EPMC8154325 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Overexpression of efflux pumps is one of the major determinants of resistance in bacteria. Streptomyces species harbor a large array of efflux pumps that are transcriptionally silenced under laboratory conditions. However, their dissemination results in multidrug resistance in different clinical pathogens. In this study, we have identified an efflux pump from Streptomyces coelicolor, SCO4121, belonging to the major facilitator superfamily (MFS) family of transporters and characterized its role in antibiotic resistance. SCO4121 provided resistance to multiple dissimilar drugs upon overexpression in both native and heterologous hosts. Further, deletion of SCO4121 resulted in increased sensitivity toward ciprofloxacin and chloramphenicol, suggesting the pump to be a major transporter of these substrates. Apart from providing multidrug resistance, SCO4121 imparted increased tolerance against the strong oxidant HOCl. In wild-type Streptomyces coelicolor cells, these drugs were found to transcriptionally regulate the pump in a concentration-dependent manner. Additionally, we identified SCO4122, a MarR regulator that positively regulates SCO4121 in response to various drugs and the oxidant HOCl. Thus, through these studies we present the multiple roles of SCO4121 in S. coelicolor and highlight the intricate mechanisms via which it is regulated in response to antibiotics and oxidative stress.IMPORTANCE One of the key mechanisms of drug resistance in bacteria is overexpression of efflux pumps. Streptomyces species are a reservoir of a large number of efflux pumps, potentially to provide resistance to both endogenous and nonendogenous antibiotics. While many of these pumps are not expressed under standard laboratory conditions, they result in resistance to multiple drugs when spread to other bacterial pathogens through horizontal gene transfer. In this study, we have identified a widely conserved efflux pump SCO4121 from Streptomyces coelicolor with roles in both multidrug resistance and oxidative stress tolerance. We also report the presence of an adjacent MarR regulator, SCO4122, which positively regulates SCO4121 in the presence of diverse substrates in a redox-responsive manner. This study highlights that soil bacteria such as Streptomyces can reveal novel mechanisms of antibiotic resistance that may potentially emerge in clinically important bacteria.

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Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS).

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