{"title":"KKL-35 通过系统地改变细菌表型来抑制金黄色葡萄球菌的生长。","authors":"Jie Xu, Zilan Wei, Wendong Fang, Jiahui Wu, Youliang Wang, Shuiping Chen","doi":"10.1007/s00203-024-04079-0","DOIUrl":null,"url":null,"abstract":"<div><p>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 <i>Staphylococcus aureus</i> (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 H<sub>2</sub>O<sub>2</sub> than DMSO (21.03 ± 2.60% vs. 68.21 ± 5.31% for NaCl, 4.91 ± 3.14% vs. 74.78 ± 2.88% for H<sub>2</sub>O<sub>2</sub>). 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<sup>2</sup>, 12.80 ± 1.03% vs. 31.99 ± 5.99% for 7.0 J/m<sup>2</sup>, 1.52 ± 0.63% vs. 6.49 ± 0.51% for 14.0 J/m<sup>2</sup>). 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.</p></div>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"KKL-35 inhibits growth of Staphylococcus aureus by systematically changing bacterial phenotypes\",\"authors\":\"Jie Xu, Zilan Wei, Wendong Fang, Jiahui Wu, Youliang Wang, Shuiping Chen\",\"doi\":\"10.1007/s00203-024-04079-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 <i>Staphylococcus aureus</i> (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 H<sub>2</sub>O<sub>2</sub> than DMSO (21.03 ± 2.60% vs. 68.21 ± 5.31% for NaCl, 4.91 ± 3.14% vs. 74.78 ± 2.88% for H<sub>2</sub>O<sub>2</sub>). 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<sup>2</sup>, 12.80 ± 1.03% vs. 31.99 ± 5.99% for 7.0 J/m<sup>2</sup>, 1.52 ± 0.63% vs. 6.49 ± 0.51% for 14.0 J/m<sup>2</sup>). 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.</p></div>\",\"PeriodicalId\":2,\"journal\":{\"name\":\"ACS Applied Bio Materials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-07-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Applied Bio Materials\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s00203-024-04079-0\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MATERIALS SCIENCE, BIOMATERIALS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Bio Materials","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s00203-024-04079-0","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
引用次数: 0
摘要
KKL-35 是一种新型噁二唑化合物，对多种革兰氏阳性和阴性细菌具有强效的广谱抗菌活性。然而，它对细菌生长的影响尚不清楚。本研究旨在调查 KKL-35 引起的金黄色葡萄球菌（SA）表型变化，并评估 KKL-35 与 7 种医疗机构可用的抗生素组合的抗菌活性。经 KKL-35 处理的金黄色葡萄球菌在 NaCl 和 H2O2 胁迫下的存活率明显低于 DMSO（NaCl 为 21.03 ± 2.60% vs. 68.21 ± 5.31%，H2O2 为 4.91 ± 3.14% vs. 74.78 ± 2.88%）。经 KKL-35 处理的 SA 的存活率比经 DMSO 处理的明显降低（4.2 J/m2 为 23.91 ± 0.71% vs. 55.45 ± 4.70%，7.0 J/m2 为 12.80 ± 1.03% vs. 31.99 ± 5.99%，14.0 J/m2 为 1.52 ± 0.63% vs. 6.49 ± 0.51%）。与 DMSO 相比，KKL-35 能明显减少生物膜的形成（0.47 ± 0.12 vs. 1.45 ± 0.21）和血清抗性试验中细菌的存活率（42.27 ± 2.77% vs. 78.31 ± 5.64%）。KKL-35 能明显降低溴化乙锭的摄取和外流以及细胞膜的完整性。KKL-35 的细胞毒性低，抗性倾向低。KKL-35 以浓度依赖性和时间依赖性的方式抑制 SA 的生长，与现有的大多数抗生素联用时显示出相加性。KKL-35 与环丙沙星、利福平或利奈唑胺的抗生素组合比相应组合中活性最强的抗生素显著降低了细菌负荷。因此，KKL-35 可通过降低细菌对环境的适应性、生物膜的形成、膜的吸收和外流以及提高抗生素的敏感性来抑制 SA 的生长。KKL-35 的抗菌活性强、细胞毒性低、抗药性低、抗生素组合选择范围广，因此有望成为设计单药和联合疗法治疗细菌感染的新型抗生素的主要化合物。
KKL-35 inhibits growth of Staphylococcus aureus by systematically changing bacterial phenotypes
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 H2O2 than DMSO (21.03 ± 2.60% vs. 68.21 ± 5.31% for NaCl, 4.91 ± 3.14% vs. 74.78 ± 2.88% for H2O2). 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/m2, 12.80 ± 1.03% vs. 31.99 ± 5.99% for 7.0 J/m2, 1.52 ± 0.63% vs. 6.49 ± 0.51% for 14.0 J/m2). 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.
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