Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. aureus

Abstract

The paper focuses on recent achievements in the search for new chemical compounds able to inhibit multidrug resistance (MDR) mechanisms in Gram-positive pathogens. An analysis of the results of the search for new efflux pump inhibitors (EPIs) for Gram-positive bacteria, which have been performed over the last decade, indicates that almost all efforts are focused on the NorA (MFS) efflux pump in S. aureus. Considering the chemical structures of the NorA EPIs that have been identified, it can be observed that the most active agents belong to the families of compounds possessing conjugated double bonds, e.g., chalcones, piperine-like compounds, N-cinnamoylphenalkylamides or citral amide derivatives. Indole-, dihydronaphthyl-, 2-chloro-5-bromo-phenyl- or piperidine moieties seem to be profitable for the EPI properties, as well. These results, together with an increasing knowledge about a variety of efflux pumps that are involved in MDR of Gram-positive pathogens underline that further search for new EPIs should pay more attention to develop MDR efflux protein targets, including SMR, MATE, ABC or other members of the MFS family.

Synergy between antibiotics and natural agents results in increased antimicrobial activity against Staphylococcus epidermidis

“…Bacteria use efflux pumps as a self-defense mechanism to remove antibiotics from the cell. The activity through efflux pumps results in sub-lethal drug concentrations at the active site that often predisposes the organism to the development of high-level resistance against antimicrobial agents [26]. Several studies have reported the crucial role of phytochemistry in the search for effective efflux pumps inhibitors (EPIs), especially against Gram-positive bacteria such as S. aureus and S. epidermidis.…”

“…The other possible mechanism by which these natural agents might be exerting their antimicrobial effect or synergistic effect with antibiotics is through inhibition of bacterial efflux pumps [26]. Bacteria use efflux pumps as a self-defense mechanism to remove antibiotics from the cell.…”

Evaluation of Different Drugs in Down-Regulation of Efflux Pump Genes expression in Methicillin-Resistant <I>Staphylococcus aureus</I> Strains

“…Several studies have shown that increased resistance to antibiotics, biocides and dyes has been associated with NorA and NorB mediated efflux pumps (Handzlik et al, 2013;Sabatini et al, 2012;Truong-Bolduc et al, 2005;Ding et al, 2008). However, antimicrobial resistance associated with NorA and NorB efflux pumps is poorly characterized in S. aureus (Handzlik et al, 2013).…”

“…However, antimicrobial resistance associated with NorA and NorB efflux pumps is poorly characterized in S. aureus (Handzlik et al, 2013). NorA uses proton motive force to energize the transport of antimicrobial compounds across the cell membrane (Neyfakh et al, 1993).…”

“…On the other hand, NorB efflux pump is structurally similar to the efflux pumps, Blt (41%) and Bmr (30%) of B. subtilis, as well as to the NorA (30%) and QacA (39%) of S. aureus. The wide specificities of multidrug efflux systems suggested their overexpression might result in the efflux of intracellular concentrations of many such agents, causing an impact on their clinical efficacy (Handzlik et al, 2013;Truong-Bolduc et al, 2011).…”