Pharmaceutical Microbiology Department, Pharmacy Faculty, Istanbul University, Istanbul, Turkey.
Department of Chemistry, Faculty of Engineering, Istanbul University, Istanbul, Turkey.
Drug Dev Res. 2022 May;83(3):628-636. doi: 10.1002/ddr.21893. Epub 2021 Oct 20.
In our pursuit of developing the novel, potent, and selective antimicrobial agents, we managed to obtain the quinolinequinone for their antimicrobial profile with minimal inhibitory concentrations (MICs) determined against a panel of seven bacterial strains (three gram-positive and four gram-negative bacteria) and three fungi. The structure-activity relationship (SAR) for the quinolinequinone class of antimicrobials was determined. Interestingly, QQ1, QQ4, QQ6-9, QQ12, and QQ13 displayed equal antibacterial potential against S. aureus (MIC = 1.22 mg/L), respectively, to the standard positive control Cefuroxime-Na. QQ10 had the best inhibitory activity with the MIC value of 1.22 mg/L (fourfold more potent compared to reference standard Clotrimazole) against Candida albicans. On the other hand, while QQ10 is not too effective against gram-positive bacteria as much as the other analogs, QQ10 was the most effective quinolinequinones against fungi. Selected quinolinequinones were further evaluated for the mode of action, using in vitro antibiofilm activity, bactericidal activity by using time-kill curve assay, antibiofilm activity, and potential antimicrobial activity against each of 32 clinically obtained resistant strains of Gram-positive Bacteria. The results also revealed that the QQ14 had specific antifungal activity against fungi in particular C. albicans. Our results clearly showed that quinolinequinones are much more active in the inhibition of the biofilm attachment process than the inhibition of mature biofilm formation. Thus, as treatment options are narrowing for Methicillin-resistant Staphylococcus spp., Vancomycin-resistant Staphylococcus spp. daily, the quinolinequinones reported herein display promise as the lead candidates for further clinical applications against serious infections.
在开发新型、强效和选择性抗菌剂的过程中，我们成功获得了喹啉醌类化合物，其抗菌谱通过对七种细菌（三种革兰氏阳性菌和四种革兰氏阴性菌）和三种真菌的最小抑菌浓度 (MIC) 进行测定。确定了喹啉醌类抗菌剂的结构-活性关系 (SAR)。有趣的是，QQ1、QQ4、QQ6-9、QQ12 和 QQ13 对金黄色葡萄球菌 (MIC = 1.22 mg/L) 的抗菌活性相同，分别与标准阳性对照头孢呋辛钠相当。QQ10 对白色念珠菌的抑制活性最好，MIC 值为 1.22 mg/L（比参考标准克霉唑高四倍）。另一方面，虽然 QQ10 对革兰氏阳性菌的作用不如其他类似物，但 QQ10 是对抗真菌最有效的喹啉醌类化合物。进一步选择了几种喹啉醌类化合物，通过体外抗生物膜活性、使用时间杀伤曲线测定法的杀菌活性、抗生物膜活性以及对 32 株临床获得的革兰氏阳性耐药菌的潜在抗菌活性进行作用模式评估。结果还表明，QQ14 对真菌特别是白色念珠菌具有特定的抗真菌活性。我们的结果清楚地表明，喹啉醌类化合物在抑制生物膜附着过程中的活性比抑制成熟生物膜形成的活性更高。因此，随着耐甲氧西林金黄色葡萄球菌和耐万古霉素金黄色葡萄球菌等治疗选择方案的日益减少，本文报道的喹啉醌类化合物有望成为进一步临床应用于严重感染的候选药物。
