一种新型杀菌小分子 STK-35 及其衍生物 STK-66，作为体外和体内革兰氏阴性病原菌的抗菌剂,Letters in Applied Microbiology

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一种新型杀菌小分子 STK-35 及其衍生物 STK-66，作为体外和体内革兰氏阴性病原菌的抗菌剂
Letters in Applied Microbiology ( IF 2.0 ) Pub Date : 2022-02-25 , DOI: 10.1111/lam.13682
Pengfei She ₁ , Lanlan Xu ₁ , Yaqian Liu ₁ , Shasha Liu ₁ , Zehao Li ₁ , Yimin Li ₁ , Zubair Hussain ₁ , Yong Wu ₂

Affiliation

由于抗生素耐药率的增加和革兰氏阴性病原菌存留细胞的出现，迫切需要开发新的抗菌药物来解决这一问题。我们的研究结果表明，新发现的小分子 STK-35 及其衍生物 STK-66 均对包括鲍曼不动杆菌、大肠杆菌、铜绿假单胞菌和肺炎克雷伯菌在内的多种革兰氏阴性病原体表现出有效的抗菌特性。最小抑制浓度和最小杀菌浓度范围为 0·0625–8 μg ml ^-1和 0·125–16 μg ml ^-1，分别没有观察到溶血活性和哺乳动物细胞毒性。时间杀灭试验表明 STK-35/66 对革兰氏阴性病原体具有很强的杀菌活性。STK-35/66 还表现出与常规抗生素不同程度的协同抗菌活性，并表现出持久性细胞杀伤活性。此外，STK-35/66 有效地根除铜绿假单胞菌和鲍曼不动杆菌预先形成的生物膜。此外，STK-35/66 显着提高了大肠杆菌感染小鼠的存活率，并降低了腹膜炎模型的细菌负荷。简而言之，这些结果表明 STK-35/66在体外对革兰氏阴性病原菌具有抗菌活性和体内，在进一步结构优化后可被视为治疗革兰氏阴性病原体感染的潜在替代品。

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A novel bactericidal small molecule, STK-35, and its derivative, STK-66, as antibacterial agents against Gram-negative pathogenic bacteria in vitro and in vivo

Due to the increasing rate of antibiotic resistance and the emergence of persister cells of Gram-negative pathogenic bacteria, the development of new antibacterial agents is urgently needed to deal with this problem. Our results indicated that both newly identified small molecule STK-35 and its derivative STK-66 exhibited effective antibacterial properties against a variety of Gram-negative pathogens including Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The minimal inhibitory concentrations and minimal bactericidal concentrations ranges were 0·0625–8 μg ml⁻¹ and 0·125–16 μg ml⁻¹, respectively, while no haemolytic activity and mammalian cell cytotoxicity were observed. The time-killing assays showed STK-35/66 had strong bactericidal activity against Gram-negative pathogens. STK-35/66 also showed different degrees of synergistic antibacterial activity with conventional antibiotics and exhibited persister cells killing activity. Moreover, STK-35/66 effectively eradicated the pre-formed biofilms of P. aeruginosa and A. baumannii. In addition, STK-35/66 significantly increased the survival rate of E. coli infected mice and induced a decrease in bacterial load of the peritonitis model. In nutshell, these results suggested that STK-35/66 possessed antimicrobial activity against Gram-negative pathogenic bacteria in vitro and in vivo, which could be considered as potential substitutes for the treatment of Gram-negative pathogenic infections after further structure optimization.

更新日期：2022-02-25

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