Promising FDA-approved drugs with efflux pump inhibitory activities against clinical isolates of Staphylococcus aureus

Abstract

Background and objectives Staphylococcus aureus is an opportunistic pathogen that causes wide range of nosocomial and community-acquired infections which have spread worldwide leading to an urgent need for developing effective anti-staphylococcal agents. Efflux is an important resistance mechanism that bacteria used to fight the antimicrobial action. This study aimed to investigate the efflux mechanism in S. aureus and assess diclofenac, domperidone, glyceryl trinitrate and metformin as potential efflux pump inhibitors that can be used in combination with antibiotics for treating topical infections caused by S. aureus. Materials and methods Efflux was detected qualitatively by the ethidium bromide Cart-Wheel method followed by investigating the presence of efflux genes by polymerase chain reaction. Twenty-six isolates were selected for further investigation of efflux by Cart-Wheel method in absence and presence of tested compounds followed by quantitative efflux assay. Furthermore, antibiotics minimum inhibitory concentrations in absence and presence of tested compounds were determined. The effects of tested drugs on expression levels of efflux genes norA, fexA and tetK were determined by quantitative real time-polymerase chain reaction. Results Efflux was found in 65.3% of isolates, the prevalence of norA, tetK, fexA and msrA genes were 91.7%, 77.8%, 27.8% and 6.9%. Efflux assay revealed that tested drugs had potential efflux inhibitory activities, reduced the antibiotic’s MICs and significantly decreased the relative expression of efflux genes. Conclusion Diclofenac sodium, domperidone and glyceryl trinitrate showed higher efflux inhibitory activities than verapamil and metformin. To our knowledge, this is the first report that shows that diclofenac sodium, glyceryl trinitrate and domperidone have efflux pump inhibitory activities against S. aureus.

Progress in the Prevalence, Classification and Drug Resistance Mechanisms of Methicillin-Resistant Staphylococcus aureus

“…And it has reported that secondary active transporters are highly substrate specific and their recognition sites are often antimicrobial drug targets ( Figure 5 and Table 5 ). 111 …”

“…And it has reported that secondary active transporters are highly substrate specific and their recognition sites are often antimicrobial drug targets (Figure 5 and Table 5). 111 MFS is the largest and most diverse membrane protein transport family, as well as the most well-studied efflux pump, which mainly includes norA, norB, norC, tet(K), tetL, mdeA, sdrM, qacA/B and other genes. Members of MFS have 12/ 14 monomeric proteins with transmembrane-spanning (TMS) helices ranging from 388 to 600 amino acids in length.…”

Structure Elucidation and Interaction Dynamics of MefA-MsrD Efflux Proteins in Streptococcus pneumoniae: Impact on Macrolide Susceptibility

“…Researchers have explored potential FDA-approved EPIs against clinical Staphylococcus aureus, as well as natural compounds to target MefA/E-pumps in drug-resistant bacteria; however, the same were not translated clinically. − The structural insights from the present study can be instrumental in phenotypic studies on macrolide resistance in pneumococci and also in designing potent EPIs translatable to the clinics.…”

Types and Mechanisms of Efflux Pump Systems and the Potential of Efflux Pump Inhibitors in the Restoration of Antimicrobial Susceptibility, with a Special Reference to Acinetobacter baumannii

“…So far, there is limited research on model organisms to test EPIs, and there is limited data from patients to show that EPIs can be successfully used. So far, C. elegans , G. melonella , D. melanogaster , and zebrafish have been successfully used as model organisms to study various efflux pumps, while murine models showed mixed results [ 140 , 167 , 168 , 169 , 170 ].…”