Modulation of antimicrobial efflux pumps of the major facilitator superfamily in <em>Staphylococcus aureus</em>

Abstract

Variants of the microorganism Staphylococcus aureus which are resistant to antimicrobial agents exist as causative agents of serious infectious disease and constitute a considerable public health concern. One of the main antimicrobial resistance mechanisms harbored by S. aureus pathogens is exemplified by integral membrane transport systems that actively remove antimicrobial agents from bacteria where the cytoplasmic drug targets reside, thus allowing the bacteria to survive and grow. An important class of solute transporter proteins, called the major facilitator superfamily, includes related and homologous passive and secondary active transport systems, many of which are antimicrobial efflux pumps. Transporters of the major facilitator superfamily, which confer antimicrobial efflux and bacterial resistance in S. aureus , are good targets for development of resistance-modifying agents, such as efflux pump inhibition. Such modulatory action upon these antimicrobial efflux systems of the major facilitator superfamily in S. aureus may circumvent resistance and restore the clinical efficacy of therapy towards S. aureus infection.

Prevalence and Therapies of Antibiotic-Resistance in Staphylococcus aureus

“…The active efflux system of bacteria was discovered in 1980 by Ball and McMurry when studying the resistance of Escherichia coli to tetracycline (Seifi and Khoshbakht, 2016). Afterwards, the scholars conducted many experiments on the active efflux system, which confirmed that the active efflux system is a normal physiological structure of bacteria, and exists in sensitive strains (Lekshmi et al, 2018). When induced by substrates in the environment for a long time, efflux system-encoding genes are activated and expressed, and the ability to efflux drugs is greatly enhanced, thus leading to drug resistance (Zarate et al, 2019).…”

Functional and Structural Roles of the Major Facilitator Superfamily Bacterial Multidrug Efflux Pumps

“…Due to their widespread occurrence among cells from across all known living taxa and because of their ability to confer multiple antimicrobial resistance, bacterial multidrug efflux pumps from the major facilitator superfamily make suitable targets for resistance modulation [38,89,122]. A variety of efflux pump modulators have been discovered, such as naturally-occurring bioactive agents [123,124], synthetic agents [125], and synergistic modulator combinations [126].…”

“…Since this groundbreaking study, CCCP has been used as a means of establishing the ion-driven process of energization for most newly discovered secondary active transport systems [7,158]. Furthermore, CCCP has been shown to be effective, albeit in an indirect manner, as an inhibitor of antimicrobial efflux in a great variety of major facilitator superfamily transporters by collapsing the proton motive force [38,89,122]. Along these lines, reserpine and piperine have served as general inhibitors for many efflux pumps, independent of the mode of energy, substrates, and superfamily membership [159][160][161].…”

Anandamide alters the membrane properties, halts the cell division and prevents drug efflux in multidrug resistant Staphylococcus aureus

“…The multidrug efflux systems are classified into five families according to their energy requirements and structures 15 . The major facilitator superfamily (MFS), the small multidrug resistance (SMR) family, the multidrug and toxic compound extrusion (MATE) family, and the resistance-nodulation-cell division (RND) superfamily use the proton motive force to drive the extrusion of their substrates by an anti-port H + :drug mechanism 15 , 16 . The MATE transporters can also use Na + membrane gradient instead of H + 15 , 16 .…”

“…The major facilitator superfamily (MFS), the small multidrug resistance (SMR) family, the multidrug and toxic compound extrusion (MATE) family, and the resistance-nodulation-cell division (RND) superfamily use the proton motive force to drive the extrusion of their substrates by an anti-port H + :drug mechanism 15 , 16 . The MATE transporters can also use Na + membrane gradient instead of H + 15 , 16 . On the other hand, the transporters of the adenosine-triphosphate (ATP)-binding cassette (ABC) superfamily use ATP to drive the extrusion of their substrates 15 , 16 .…”