Laboratório de Microbiologia Médica, Universidade Federal de São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil.
Laboratório de Microbiologia Médica, Universidade Federal de São João del-Rei (UFSJ), Campus Centro-Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil.
Microbiol Res. 2022 Aug;261:127073. doi: 10.1016/j.micres.2022.127073. Epub 2022 May 16.
Staphylococcus aureus is a Gram-positive bacterium responsible for a wide variety of infectious diseases, and its methicillin-resistant isolates pose a serious worldwide public health risk. New drugs are urgently needed for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we evaluated the antibacterial activity of five 3-alkyl-pyridinic analogs against MRSA and, of these compounds, compound 6 showed promising antibacterial activity against Staphylococcus with minimum inhibitory concentration (MIC) ranging from 0.98 to 3.9 μgmL¹ . In addition, it exhibited a rapid bactericidal action, with complete elimination of MRSA after 6 h of incubation at 15.6 μgmL¹ . Compound 6 had the ability to damage the bacterial membrane and induce cell lysis and, due to its action on the membrane, showed low resistance induction potential in vitro. In the combination study, compound 6 revealed an additive effect (FICI = 1) with vancomycin and ofloxacin and ciprofloxacin (FICI = 0.75) against MRSA, reducing the effective concentration of this antibiotic two-fold. The anti-staphylococcal activity of compound 6 was stable in the presence of different concentrations of NaCl (50, 200, and 400 µM), trypsin ( 1:500, 1:250) and under a variety of pH values (4, 5, 6, and 8); however, its binding to plasmatic proteins (i.e., albumin) was substantial. The previous exposure of MRSA to the compound was able to reduce the formation of bacterial biofilm and reduce the biomass of mature biofilms. Compound 6 showed low selectivity in vitro for MRSA USA 300 when compared to eukaryotic cells (epithelial, fibroblast, and red blood cells).
金黄色葡萄球菌是一种革兰氏阳性细菌，可导致多种传染病，其耐甲氧西林分离株对全球公共卫生构成严重威胁。目前急需新型药物来治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染。在此，我们评估了五种 3-烷基-吡啶类似物对 MRSA 的抗菌活性，其中化合物 6 对金黄色葡萄球菌表现出有前景的抗菌活性，最低抑菌浓度（MIC）范围为 0.98 至 3.9 μgmL¹。此外，它表现出快速杀菌作用，在 15.6 μgmL¹浓度下孵育 6 小时后可完全消除 MRSA。化合物 6 具有破坏细菌膜并诱导细胞裂解的能力，由于其对膜的作用，在体外显示出低的耐药诱导潜力。在联合研究中，化合物 6 与万古霉素和氧氟沙星以及环丙沙星（FICI = 0.75）联合使用对 MRSA 表现出相加作用（FICI = 1），使该抗生素的有效浓度降低了两倍。在存在不同浓度的 NaCl（50、200 和 400 µM）、胰蛋白酶（1:500、1:250）和不同 pH 值（4、5、6 和 8）的情况下，化合物 6 的抗葡萄球菌活性均保持稳定；然而，它与血浆蛋白（即白蛋白）的结合量很大。MRSA 先前暴露于该化合物能够减少细菌生物膜的形成并降低成熟生物膜的生物量。与真核细胞（上皮细胞、成纤维细胞和红细胞）相比，化合物 6 对 MRSA USA 300 的体外选择性较低。
