Efflux Pump (QacA, QacB, and QacC) and β-Lactamase Inhibitors? An Evaluation of 1,8-Naphthyridines against Staphylococcus aureus Strains

Abstract

The bacterial species Staphylococcus aureus presents a variety of resistance mechanisms, among which the expression of β-lactamases and efflux pumps stand out for providing a significant degree of resistance to clinically relevant antibiotics. The 1,8-naphthyridines are nitrogen heterocycles with a broad spectrum of biological activities and, as such, are promising research targets. However, the potential roles of these compounds on bacterial resistance management remain to be better investigated. Therefore, the present study evaluated the antibacterial activity of 1,8-naphthyridine sulfonamides, addressing their ability to act as inhibitors of β-lactamases and efflux pump (QacA/B and QacC) against the strains SA-K4414 and SA-K4100 of S. aureus. All substances were prepared at an initial concentration of 1024 μg/mL, and their minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. Subsequently, their effects on β-lactamase- and efflux pump-mediated antibiotic resistance was evaluated from the reduction of the MIC of ethidium bromide (EtBr) and β-lactam antibiotics, respectively. The 1,8-naphthyridines did not present direct antibacterial activity against the strains SA-K4414 and SA-K4100 of S. aureus. On the other hand, when associated with antibiotics against both strains, the compounds reduced the MIC of EtBr and β-lactam antibiotics, suggesting that they may act by inhibiting β-lactamases and efflux pumps such as QacC and QacA/B. However, further research is required to elucidate the molecular mechanisms underlying these observed effects.

In vitro antimicrobial mechanism of diacerein and potential to reverse MRSE resistance to β-lactams

“…However, previous studies have shown that interior membrane transporter actively capture drugs and exclude them out [22] . Therefore, the active efflux system also plays a certain role in the mechanism of bacterial resistance to β-lactam drugs, especially the ABC transports [23] .…”

“…Due to the poor permeability of the bacterial intima to β-lactams, these tend to accumulate in the Intermembrane space and act on the target proteins. However, previous studies have shown that interior membrane transporter actively capture drugs and exclude them out [22] . Therefore, the active efflux system also plays a certain role in the mechanism of bacterial resistance to β-lactam drugs, especially the ABC transports [23] .…”

Inhibition of Multidrug Efflux Pumps Belonging to the Major Facilitator Superfamily in Bacterial Pathogens

“…Interestingly, evaluation of the 1,8-naphthyridine sulfonamides showed that they could inhibit both β-lactamases and the QacC and QacA/B efflux pumps in S. aureus [101]. Thus, these agents and their derivatives show promise in addressing infection by pathogens by targeting more than one resistance mechanism, as in the case of resistances conferred by enzymatic inactivation and active drug efflux.…”