Kaldalu Niilo, Bērziņš Normunds, Berglund Fick Stina, Sharma Atin, Andersson Naomi Charlotta, Aedla Jüri, Hinnu Mariliis, Puhar Andrea, Hauryliuk Vasili, Tenson Tanel
Institute of Technology, University of Tartu, Tartu, Estonia.
Chemical Biology Consortium Sweden, Umeå University, Umeå, Sweden.
NPJ Antimicrob Resist. 2025 Apr 11;3(1):25. doi: 10.1038/s44259-025-00097-0.
Slow- and non-growing bacterial populations, along with intracellular pathogens, often evade standard antibacterial treatments and are linked to persistent and recurrent infections. This necessitates the development of therapies specifically targeting nonproliferating bacteria. To identify compounds active against non-growing uropathogenic Escherichia coli (UPEC) we performed a drug-repurposing screen of 6454 approved drugs and drug candidates. Using dilution-regrowth assays, we identified 39 compounds that either kill non-growing UPEC or delay its regrowth post-treatment. The hits include fluoroquinolones, macrolides, rifamycins, biguanide disinfectants, a pleuromutilin, and anti-cancer agents. Twenty-nine of the hits have not previously been recognized as active against non-growing bacteria. The hits were further tested against non-growing Pseudomonas aeruginosa and Staphylococcus aureus. Ten compounds - solithromycin, rifabutin, mitomycin C, and seven fluoroquinolones-have strong bactericidal activity against non-growing P. aeruginosa, killing >4 log of bacteria at 2.5 µM. Solithromycin, valnemulin, evofosfamide, and satraplatin are unique in their ability to selectively target non-growing bacteria, exhibiting poor efficacy against growing bacteria. Finally, 31 hit compounds inhibit the growth of intracellular Shigella flexneri in a human enterocyte infection model, indicating their ability to permeate the cytoplasm of host cells. The identified compounds hold potential for treating persistent infections, warranting further comparative studies with current standard-of-care antibiotics.
生长缓慢和不生长的细菌群体，以及细胞内病原体，常常逃避标准的抗菌治疗，并与持续性和复发性感染有关。这就需要开发专门针对不增殖细菌的疗法。为了确定对不生长的尿路致病性大肠杆菌（UPEC）有活性的化合物，我们对6454种已批准的药物和候选药物进行了药物再利用筛选。通过稀释再生长试验，我们鉴定出39种化合物，它们要么能杀死不生长的UPEC，要么能延缓其治疗后的再生长。这些命中的化合物包括氟喹诺酮类、大环内酯类、利福霉素类、双胍类消毒剂、截短侧耳素类以及抗癌药物。其中有29种命中的化合物此前未被认为对不生长的细菌有活性。这些命中的化合物进一步针对不生长的铜绿假单胞菌和金黄色葡萄球菌进行了测试。十种化合物——索利霉素、利福布汀、丝裂霉素C以及七种氟喹诺酮类——对不生长的铜绿假单胞菌有很强的杀菌活性，在2.5µM时能杀死>4个对数级的细菌。索利霉素、伐地那非、依沃福酰胺和沙铂在选择性靶向不生长细菌方面具有独特能力，对生长中的细菌疗效不佳。最后，31种命中的化合物在人肠上皮细胞感染模型中抑制细胞内福氏志贺菌的生长，表明它们能够渗透到宿主细胞的细胞质中。所鉴定出的化合物在治疗持续性感染方面具有潜力，值得与当前的标准护理抗生素进行进一步的比较研究。
