Department of Laboratory Medicine, The PLA 307 Clinical College, 5th Clinical Medical College of Anhui Medical University, Beijing, China.
Department of Laboratory Medicine, 5th Medical Center of Chinese PLA General Hospital, Beijing, China.
Arch Microbiol. 2024 Jul 12;206(8):350. doi: 10.1007/s00203-024-04079-0.
KKL-35 is a new oxadiazole compound with potent broad-spectrum antibacterial activity against a number of gram-positive and gram-negative bacteria. However, its influences on bacterial growth are unclear. This study is to investigate phenotypic changes of Staphylococcus aureus (SA) caused by KKL-35 and evaluate antibacterial activity of combinations of KKL-35 with 7 class of antibiotics available in medical facilities. KKL-35-treated SA showed significantly lower survival under stresses of NaCl and HO than DMSO (21.03 ± 2.60% vs. 68.21 ± 5.31% for NaCl, 4.91 ± 3.14% vs. 74.78 ± 2.88% for HO). UV exposure significantly decreased survival of SA treated with KKL-35 than DMSO-treated ones (23.91 ± 0.71% vs. 55.45 ± 4.70% for 4.2 J/m, 12.80 ± 1.03% vs. 31.99 ± 5.99% for 7.0 J/m, 1.52 ± 0.63% vs. 6.49 ± 0.51% for 14.0 J/m). KKL-35 significantly decreased biofilm formation (0.47 ± 0.12 vs. 1.45 ± 0.21) and bacterial survival in the serum resistance assay (42.27 ± 2.77% vs. 78.31 ± 5.64%) than DMSO. KKL-35 significantly decreased ethidium bromide uptake and efflux, as well as the cell membrane integrity. KKL-35 had low cytotoxicity and low propensity for resistance. KKL-35 inhibited SA growth in concentration-independent and time-dependent manners, and showed additivity when combined with the majority class of available antibiotics. Antibiotic combinations of KKL-35 with ciprofloxacin, rifampicin, or linezolid significantly decreased bacterial loads than the most active antibiotic in the corresponding combination. Thus, KKL-35 inhibits growth of SA by decreasing bacterial environmental adaptations, biofilm formation, membrane uptake and efflux, as well as increasing antibiotic sensitivity. Its potent antibacterial activity, low cytotoxicity, low propensity for resistance, and wide choices in antibiotic combinations make KKL-35 a promising leading compound to design new antibiotics in monotherapies and combination therapies to treat bacterial infections.
KKL-35 是一种新的恶二唑化合物，对许多革兰氏阳性和革兰氏阴性细菌具有广谱的强大抗菌活性。然而，其对细菌生长的影响尚不清楚。本研究旨在探讨 KKL-35 引起金黄色葡萄球菌（SA）表型变化，并评估 KKL-35 与医疗机构中可用的 7 类抗生素联合使用的抗菌活性。与 DMSO 相比，用 KKL-35 处理的 SA 在 NaCl 和 HO 应激下的存活能力明显降低（NaCl 为 21.03±2.60%，HO 为 4.91±3.14%）。紫外线照射使用 KKL-35 处理的 SA 的存活能力明显低于用 DMSO 处理的 SA（4.2 J/m 时为 23.91±0.71%，7.0 J/m 时为 12.80±1.03%，14.0 J/m 时为 1.52±0.63%）。与 DMSO 相比，KKL-35 显著降低了生物膜形成（0.47±0.12 对 1.45±0.21）和血清耐药试验中细菌的存活能力（42.27±2.77%对 78.31±5.64%）。KKL-35 显著降低了溴化乙锭摄取和外排以及细胞膜完整性。KKL-35 细胞毒性低，耐药性低。KKL-35 以浓度非依赖性和时间依赖性方式抑制 SA 生长，并与大多数可用抗生素联合使用时表现出相加作用。与相应组合中最有效的抗生素相比，KKL-35 与环丙沙星、利福平或利奈唑胺的抗生素组合可显著降低细菌负荷。因此，KKL-35 通过降低细菌环境适应性、生物膜形成、膜摄取和外排以及增加抗生素敏感性来抑制 SA 的生长。其强大的抗菌活性、低细胞毒性、低耐药倾向以及抗生素联合治疗的广泛选择，使 KKL-35 成为设计新抗生素的有前途的先导化合物，无论是单独使用还是联合使用，均可用于治疗细菌感染。
