Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition

Abstract

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use.

Advances in Nanostructures for Antimicrobial Therapy

“…The advantages of using lipid-based NCs, surface modification methods to enhance the efficiency and stability of phage-loaded liposomes, preparation of multiple nanoemulsions suitable for phage cocktails, phage loaded nanofibers; advanced core shell nanofibers enabling immediate, biphasic and delayed release as well as smart phage release delivery platforms were discussed [ 83 , 84 , 85 , 86 ]. Bacterial resistance is associated with the overexpression of relative activities of the efflux pump and efflux transporters situated in the membrane of bacteria, which has a crucial impact on the inhibition of the intracellular drug intake and suppression of the drug activities [ 87 , 88 ]. However, the effective inhibition of transporter activity can be achieved using NPs as encapsulating agents, enabling enhanced intracellular accumulation of drugs and helping to overcome bacterial resistance.…”

Proteomic Comparison of Ivermectin Sensitive and Resistant Staphylococcus aureus Clinical Isolates Reveals Key Efflux Pumps as Possible Resistance Determinants

“…Consequently, methicillin resistant Staphylococcus aureus (MRSA) are prevalent throughout the globe [ 16 ] and they are often resistant to most of the known antibiotics. To this end, different efflux pump inhibitors have been explored as a strategy to overcome antibiotic resistance in S. aureus species [ 17 ]. Recently, our group has shown that IVM has an activity against clinical isolates of S .…”

CryoEM structure of QacA, an antibacterial efflux transporter from Staphylococcus aureus

“…The list annotates the Gram-positive pathogen, Staphylococcus aureus, as a high-priority pathogen that causes a wide array of localized or systemic infections, including bacteremia, endocarditis, and implant infections 6 . Drug-resistant strains of Staphylococcus aureus express a diverse set of MFS antiporters in their membranes, including the chromosomally encoded transporters NorA, NorB, and NorC that provide resistance against fluoroquinolones 7 , and QacA and QacB that are plasmid-encoded and are involved in antibacterial efflux 8,9 . QacA is highly prevalent in S.aureus strains resistant to cationic antibacterial compounds, particularly among those associated with nosocomial infections 10 .…”

“…The MFS transporters involved in drug:proton antiport (DHA) are divided into DHA1 and DHA2 depending on the number of transmembrane (TM) helices (12 or 14, respectively) in each transporter 11 . While transporters like NorA, MdfA, and LmrP comprise 12 TM helices and belong to the DHA1 class of transporters 12-14 , QacA, LfrA, and SmvA comprise 14 TM helices and are part of the DHA2 family 9,15,16 .…”

“…While transporters like NorA, MdfA, and LmrP comprise 12 TM helices and belong to the DHA1 class of transporters [12][13][14] , QacA, LfrA, and SmvA comprise 14 TM helices and are part of the DHA2 family 9,15,16 .…”