Abstract：
Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are difficult to treat with antibiotics alone. Therefore, there is a need for an effective S. aureus biofilm inhibitor to combat this public health threat. In this study, a small library of indolenine-substituted pyrazoles and pyrimido[1,2-b]indazole derivatives were synthesised, of which the hit compound exhibited promising antibiofilm activities against methicillin-susceptible S. aureus (MSSA ATCC 29213) and methicillin-resistant S. aureus (MRSA ATCC 33591) at concentrations significantly lower than the planktonic growth inhibition. The hit compound could prevent biofilm formation and eradicate mature biofilms of MSSA and MRSA, with a minimum biofilm inhibitory concentration (MBIC50) value as low as 1.56 µg/mL and a minimum biofilm eradication concentration (MBEC50) value as low as 6.25 µg/mL. The minimum inhibitory concentration (MIC) values of the hit compound against MSSA and MRSA were 50 µg/mL and 25 µg/mL, respectively, while the minimum bactericidal concentration (MBC) values against MSSA and MRSA were > 100 µg/mL. Preliminary structure-activity relationship analysis reveals that the fused benzene ring and COOH group of the hit compound are crucial for the antibiofilm activity. Additionally, the compound was not cytotoxic to human alveolar A549 cells, thus highlighting its potential as a suitable candidate for further development as a S. aureus biofilm inhibitor.
摘要：
金黄色葡萄球菌是一种适应性很强的机会性病原体，可以形成生物膜并产生持久细胞，导致危及生命的感染，单用抗生素很难治疗。因此,需要有效的金黄色葡萄球菌生物膜抑制剂来对抗这种公共卫生威胁。在这项研究中,合成了吲哚烯取代的吡唑和嘧啶并[1,2-b]吲哚衍生物的小文库，其中命中化合物对甲氧西林敏感的金黄色葡萄球菌（MSSAATCC29213）和耐甲氧西林的金黄色葡萄球菌（MRSAATCC33591）的浓度显着低于浮游生物生长抑制。该化合物可以防止生物膜形成并根除MSSA和MRSA的成熟生物膜，最小生物膜抑制浓度（MBIC50）值低至1.56µg/mL，最小生物膜根除浓度（MBEC50）值低至6.25µg/mL。击中化合物对MSSA和MRSA的最小抑制浓度（MIC）值分别为50µg/mL和25µg/mL，分别,而针对MSSA和MRSA的最小杀菌浓度（MBC）值>100µg/mL。初步的构效关系分析表明，命中化合物的稠合苯环和COOH基团对抗生物膜活性至关重要。此外,该化合物对人肺泡A549细胞无细胞毒性，从而突出了其作为进一步开发金黄色葡萄球菌生物膜抑制剂的合适候选者的潜力。
