The Major Facilitator Superfamily and Antimicrobial Resistance Efflux Pumps of the ESKAPEE Pathogen Staphylococcus aureus

Abstract

The ESKAPEE bacterial pathogen Staphylococcus aureus has posed a serious public health concern for centuries. Throughout its evolutionary course, S. aureus has developed strains with resistance to antimicrobial agents. The bacterial pathogen has acquired multidrug resistance, causing, in many cases, untreatable infectious diseases and raising serious public safety and healthcare concerns. Amongst the various mechanisms for antimicrobial resistance, integral membrane proteins that serve as secondary active transporters from the major facilitator superfamily constitute a chief system of multidrug resistance. These MFS transporters actively export structurally different antimicrobial agents from the cells of S. aureus. This review article discusses the S. aureus-specific MFS multidrug efflux pump systems from a molecular mechanistic perspective, paying particular attention to structure-function relationships, modulation of antimicrobial resistance mediated by MFS drug efflux pumps, and direction for future investigation.

Keywords: ESKAPEE; Staphylococcus aureus; bacterial pathogens; major facilitator superfamily; multidrug efflux; multidrug resistance; transporter proteins.

Figure 1

Topology of QacA. The transporters of the MFS have 12 to 14 transmembrane helices. Shown here is the two-dimensional structure of the multidrug efflux pump QacA, a well-studied MFS transporter from S. aureus [51].

Figure 2

Ion-driven antiport mechanism of MFS multidrug efflux pumps. The oval cylinders represent the two N- and C-terminal bundles, surrounded by shaded purple and brown space-filling three-dimensional structures. Protons are denoted as encircled H⁺. The pink cylinder represents an enhanced affinity for the proton. The multicolored capsules depict antimicrobial agents. The mechanism described is based on studies summarized in references [62,63]. Steps 1–5 depict the following. 1: Outward open configuration of an empty MFS efflux pump. 2: The binding of H⁺ ion on the outside increases the drug binding affinity inside in an inward occluded state. 3: Intermediate occluded state. 4: Movement of the drug across the membrane to the outside and the H⁺ ion inside the bacterial cell. 5: Intermediate empty occluded state.

Figure 3

Modulation of MFS efflux pump by efflux pump inhibitors (EPIs) in S. aureus. 1: Downregulation of genes encoding an efflux pump. 2: Disruption of the membrane potential. 3: Interaction of EPIS with antimicrobials. 4: Disruption and impediment of efflux pump assemblies and membrane-bound proteins. 5: Competitive and non-competitive inhibition by EPIs. 6: Chelation of Ca²⁺ ions by EPIs in some specific efflux pumps, such as LmrS of S. aureus [117].