Roy Sweta, Cakmak Zeynep S, Kyeremeh Sheila Priscilla, Nangia Shikha, Luo Juntao, Ren Dacheng
Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, New York, USA.
Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA.
Antimicrob Agents Chemother. 2025 Sep 3;69(9):e0181424. doi: 10.1128/aac.01814-24. Epub 2025 Jul 31.
Conventional antibiotic drug discovery selects leads based on bacterial growth inhibition. This approach is ineffective against growth-arrested persister cells. When the treatment stops, persister cells revert to normal cells, causing the infection to relapse. To address the challenge of persistent infections, a paradigm shift in antibiotic development is needed to identify new leads that can eradicate dormant cells. Based on our foundational study, we recently proposed a set of principles for developing new persister killing agents. Here, we report the discovery of new leads that are effective against persister cells using a tailored chemoinformatic clustering algorithm based on these principles. We focused on persister penetration using a small compound library that has known antimicrobial activities against normal cells. Experimental testing of eleven compounds identified from clustering led to the discovery of five new compounds that can effectively penetrate and kill persister cells of HM22. The top leads were further tested and also found active against persister cells of and uropathogenic (UPEC), as well as UPEC biofilms and biofilm-associated persister cells. This rather high yield demonstrates the potential of this new rational approach in identifying effective agents against dormant cells, a root cause of persistent infections that is largely missed in conventional screening.
传统的抗生素药物研发是基于细菌生长抑制来筛选先导化合物。这种方法对生长停滞的持留菌细胞无效。当治疗停止时，持留菌细胞会恢复为正常细胞，导致感染复发。为应对持续性感染的挑战，抗生素研发需要范式转变，以识别能够根除休眠细胞的新先导化合物。基于我们的基础研究，我们最近提出了一套开发新型持留菌杀伤剂的原则。在此，我们报告基于这些原则，使用定制的化学信息聚类算法发现了对持留菌细胞有效的新先导化合物。我们使用一个对正常细胞具有已知抗菌活性的小分子化合物库，专注于持留菌的渗透。对从聚类中鉴定出的11种化合物进行实验测试，发现了5种能够有效渗透并杀死HM22持留菌细胞的新化合物。对最佳先导化合物进一步测试，发现它们对大肠杆菌和尿路致病性大肠杆菌（UPEC）的持留菌细胞以及UPEC生物膜和生物膜相关持留菌细胞也有活性。如此高的成功率表明这种新的合理方法在识别针对休眠细胞的有效药物方面具有潜力，而休眠细胞是持续性感染的根本原因，在传统筛选中很大程度上被忽视了。
