Mechanobiology Institute, National University of Singapore, Singapore, Singapore.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Antimicrob Agents Chemother. 2022 Oct 18;66(10):e0059722. doi: 10.1128/aac.00597-22. Epub 2022 Sep 12.
Frequent outbreaks of Salmonella Typhimurium infection, in both animal and human populations and with the potential for zoonotic transmission, pose a significant threat to the public health sector. The rapid emergence and spread of more invasive multidrug-resistant clinical isolates of Salmonella further highlight the need for the development of new drugs with effective broad-spectrum bactericidal activities. The synthesis and evaluation of main-chain cationic polyimidazolium 1 (PIM1) against several Gram-positive and Gram-negative bacteria have previously demonstrated the efficacy profile of PIM1. The present study focuses on the antibacterial and anti-biofilm activities of PIM1 against Salmonella in both and settings. PIM1 exhibited bactericidal activity against three strains of Salmonella at a low dosage of 8 μg/mL. The anti-biofilm activity of PIM1 was evident by its elimination of planktonic cells within preformed biofilms in a dose-dependent manner. During the host cell infection process, PIM1 reduces the extracellular bacterial load, which reduces adhesion and invasion to limit the establishment of infection. Once intracellular, Salmonella strains were tolerant and protected from PIM1 treatment. In a chicken egg infection model, PIM1 exhibited therapeutic activity for both Salmonella strains, using stationary-phase and exponential-phase inocula. Moreover, PIM1 showed a remarkable efficacy against the stationary-phase inocula of drug-resistant Salmonella by eliminating the bacterial burden in >50% of the infected chicken egg embryos. Collectively, our results highlight the potential for PIM1 as a replacement therapy for existing antibiotic applications on the poultry farm, given the efficiency and low toxicity profile demonstrated in our agriculturally relevant chicken embryo model.
鼠伤寒沙门氏菌感染频繁爆发，无论是在动物还是人类群体中，都存在动物源性传播的潜在风险，这对公共卫生部门构成了重大威胁。具有潜在动物源性传播风险的鼠伤寒沙门氏菌感染频繁爆发，且越来越多的临床分离株具有侵袭性和多重耐药性，这进一步强调了开发具有有效广谱杀菌活性的新药的必要性。先前已经合成并评价了主链阳离子聚咪唑啉 1（PIM1）对几种革兰氏阳性和革兰氏阴性细菌的作用，结果表明 PIM1 具有有效的杀菌作用。本研究重点研究了 PIM1 在 和 条件下对沙门氏菌的抗菌和抗生物膜活性。结果表明，低剂量 8μg/mL 的 PIM1 对 3 株鼠伤寒沙门氏菌具有杀菌活性。PIM1 以剂量依赖的方式消除浮游细胞，从而消除了预先形成的生物膜中的浮游细胞，表现出抗生物膜活性。在宿主细胞感染过程中，PIM1 减少了胞外细菌负荷，从而减少了细菌的黏附和侵袭，限制了感染的建立。一旦进入细胞内，沙门氏菌菌株对 PIM1 治疗具有耐受性和保护作用。在鸡胚感染模型中，PIM1 对两种鼠伤寒沙门氏菌的静止期和指数期接种物均表现出治疗活性。此外，PIM1 对耐药性鼠伤寒沙门氏菌的静止期接种物具有显著疗效，可消除>50%感染鸡胚中的细菌负荷。综上所述，鉴于我们在农业相关鸡胚模型中观察到的效率和低毒性特征，PIM1 有可能替代现有抗生素在禽类养殖场中的应用。
