The antibacterial activity and mechanisms of Trp-containing peptides against multidrug-resistant Pseudomonas aeruginosa persisters

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mengmiao Li , Xiaomi Sun , Lei Zhao , Wanying Du , Dejing Shang
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Abstract

Bacterial persisters avoid antibiotic-mediated death by entering a dormant state and are considered a major cause of antibiotic treatment failure. Antimicrobial peptides (AMPs) with membrane-disrupting activity are promising drugs to eradicate persister cells. In this study, carbonyl cyanide m-chlorophenylhydrazone (CCCP), ciprofloxacin (CIP), and rifampicin (RFP) were applied to induce the formation of multidrug-resistant Pseudomonas aeruginosa (MRPA0108) persisters, and the antibacterial activity and mechanisms of I1W and L12W (two Trp-containing peptides designed in our lab) against MRPA0108 persisters were investigated. The results showed that I1W and L12W displayed potent antibacterial activity against MRPA0108 persisters. Both Trp-containing peptides disturbed the inner and outer membrane of MRPA0108 persisters. In addition, I1W and L12W revealed novel antibacterial mechanisms by decreasing the enzymatic activities of superoxide dismutase (SOD) and catalase (CAT), increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, consequently leading to oxidative stress. The transcriptome profile of I1W-treated MRPA0108 persisters revealed that the genes involved in carbon metabolism, biosynthesis of amino acids, and the TCA cycle were downregulated, indicating that I1W interfered with metabolism and energy synthesis processes. Furthermore, both Trp-containing peptides displayed synergistic activities with antibiotic tobramycin and showed additive activities with cefepime or ciprofloxacin, which revealed a potential therapeutic strategy for the eradication of MRPA0108 persisters.

Abstract Image

含 Trp 肽对耐多药铜绿假单胞菌宿主的抗菌活性和机制。
细菌宿主通过进入休眠状态来避免抗生素介导的死亡,被认为是抗生素治疗失败的主要原因。具有膜破坏活性的抗菌肽(AMPs)是根除宿主细胞的有效药物。本研究采用间氯苯基腙(CCCP)、环丙沙星(CIP)和利福平(RFP)诱导耐多药铜绿假单胞菌(MRPA0108)宿主细胞的形成,并研究了I1W和L12W(我们实验室设计的两种含Trp的多肽)对MRPA0108宿主细胞的抗菌活性和机制。结果表明,I1W 和 L12W 对 MRPA0108 蠕虫具有很强的抗菌活性。这两种含Trp的多肽都能破坏MRPA0108宿主的内膜和外膜。此外,I1W和L12W通过降低超氧化物歧化酶(SOD)和过氧化氢酶(CAT)的酶活性,增加活性氧(ROS)和丙二醛(MDA)水平,从而导致氧化应激,揭示了新的抗菌机制。经 I1W 处理的 MRPA0108 宿主的转录组图谱显示,参与碳代谢、氨基酸生物合成和 TCA 循环的基因被下调,表明 I1W 干扰了新陈代谢和能量合成过程。此外,这两种含Trp的多肽与抗生素妥布霉素具有协同活性,与头孢吡肟或环丙沙星具有相加活性,这揭示了根除MRPA0108顽固病菌的潜在治疗策略。
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来源期刊
Biochimie
Biochimie 生物-生化与分子生物学
CiteScore
7.20
自引率
2.60%
发文量
219
审稿时长
40 days
期刊介绍: Biochimie publishes original research articles, short communications, review articles, graphical reviews, mini-reviews, and hypotheses in the broad areas of biology, including biochemistry, enzymology, molecular and cell biology, metabolic regulation, genetics, immunology, microbiology, structural biology, genomics, proteomics, and molecular mechanisms of disease. Biochimie publishes exclusively in English. Articles are subject to peer review, and must satisfy the requirements of originality, high scientific integrity and general interest to a broad range of readers. Submissions that are judged to be of sound scientific and technical quality but do not fully satisfy the requirements for publication in Biochimie may benefit from a transfer service to a more suitable journal within the same subject area.
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