RESUMO
The bacterial species Staphylococcus aureus presents a variety of resistance mechanisms, among which the expression of ß-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 ß-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 ß-lactamase- and efflux pump-mediated antibiotic resistance was evaluated from the reduction of the MIC of ethidium bromide (EtBr) and ß-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 ß-lactam antibiotics, suggesting that they may act by inhibiting ß-lactamases and efflux pumps such as QacC and QacA/B. However, further research is required to elucidate the molecular mechanisms underlying these observed effects.
Assuntos
Antibacterianos , Staphylococcus aureus , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Staphylococcus aureus/efeitos dos fármacosRESUMO
Antibiotic resistance can be characterized, in biochemical terms, as an antibiotic's inability to reach its bacterial target at a concentration that was previously effective. Microbial resistance to different agents can be intrinsic or acquired. Intrinsic resistance occurs due to inherent functional or structural characteristics of the bacteria, such as antibiotic-inactivating enzymes, nonspecific efflux pumps, and permeability barriers. On the other hand, bacteria can acquire resistance mechanisms via horizontal gene transfer in mobile genetic elements such as plasmids. Acquired resistance mechanisms include another category of efflux pumps with more specific substrates, which are plasmid-encoded. Efflux pumps are considered one of the main mechanisms of bacterial resistance to antibiotics and biocides, presenting themselves as integral membrane transporters. They are essential in both bacterial physiology and defense and are responsible for exporting structurally diverse substrates, falling into the following main families: ATP-binding cassette (ABC), multidrug and toxic compound extrusion (MATE), major facilitator superfamily (MFS), small multidrug resistance (SMR) and resistance-nodulation-cell division (RND). The Efflux pumps NorA and Tet(K) of the MFS family, MepA of the MATE family, and MsrA of the ABC family are some examples of specific efflux pumps that act in the extrusion of antibiotics. In this review, we address bacterial efflux pump inhibitors (EPIs), including 1,8-naphthyridine sulfonamide derivatives, given the pre-existing knowledge about the chemical characteristics that favor their biological activity. The modification and emergence of resistance to new EPIs justify further research on this theme, aiming to develop efficient compounds for clinical use.
Assuntos
Proteínas de Bactérias , Staphylococcus aureus , Humanos , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Sulfonamidas/farmacologia , Bactérias , Antibacterianos/farmacologia , Sulfanilamida/farmacologia , Naftiridinas/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
This study aimed to evaluate the antibacterial activity and to verify, in silico and in vitro, the inhibition of efflux mechanisms using a series of synthesized 1,8-naphthyridines sulfonamides against Staphylococcus aureus strains carrying MepA efflux pumps. The chemical synthesis occurred through the thermolysis of the Meldrum's acid adduct. The sulfonamide derivatives were obtained by the sulfonylation of 2-amino-5chloro-1,8-naphthyridine with commercial benzenesulfonyl chloride. Antibacterial activity was assessed by the broth microdilution test. Efflux pump inhibitory capacity was evaluated in silico by molecular docking and in vitro by analyzing synergistic effects on ciprofloxacin and ethidium bromide (EtBr) and by EtBr fluorescence emission assays. The following 1,8-naphthyridines were synthesized: 4-methyl-N-(5chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10a); 2,5-dichloro-N-(5chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10b); 4-fluoro-N-(5chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10c); 2,3,4-trifluoro-N-(5chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10d); 3-trifluoromethyl-N-(5chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10e); 4bromo-2,5-difluoro-N-(5chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10f). The 1,8-naphthyridines derivatives associated with sulfonamides did not show antibacterial activity. However, they showed a favorable pharmacokinetic profile with possible MepA efflux pump inhibitory action, demonstrated in molecular docking. In addition to the promising results in reducing the concentration of intracellular EtBr. 1,8-naphthyridines act as putative agents in the inhibitory action of the MepA efflux pump.