Antimicrobial peptide mimic 329 potentiates minocycline against carbapenem-resistant Klebsiella pneumoniae

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-04-25 DOI:10.1016/j.bioorg.2025.108517

Yongqing Liu , Tingting Yan , Hongtao Kong , Leizi Chi , Dejun Liu , Shangshang Qin , Yang Wang , Muchen Zhang , En Zhang

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Abstract

As antibiotic resistance increases and new drug development lags, the effectiveness of single antibiotics has drastically diminished for clinical infection treatment. The resistance crisis is exacerbated by the swift development and dissemination of Gram-negative bacteria that are extensively drug-resistant (XDR), particularly strains resistant to carbapenems in clinical settings. In this scenario, antibiotic adjuvants play a crucial role in revitalizing existing treatments to combat carbapenem-resistant bacterial infections. In this study, we synthesized ten small molecular antimicrobial peptide mimics and identified antimicrobial peptide mimic 329 (A329), which exhibited a synergistic effect with minocycline (FICI = 0.023), enhancing its efficacy by 4- to 128-fold, and significantly enhanced the antibacterial efficacy of minocycline against carbapenem-resistant Klebsiella pneumoniae (CRKP, 0.015 ≤ FICI ≤0.141), prevented the emergence of minocycline resistance, improved the survival rate of mice, and decreased bacterial load in tissues at 8 + 8 mg/kg. Mechanistic studies revealed that A329 increases bacterial membrane permeability and disrupts the proton-motive force. Additionally, A329 combined with minocycline boosts intracellular minocycline accumulation, induces intracellular production of reactive oxygen species (ROS), and ultimately triggers bacterial death. These findings advised that A329 in combination with minocycline is a potential combination therapy against XDR-associated infections.

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抗菌肽模拟物329增强米诺环素对抗耐碳青霉烯肺炎克雷伯菌

随着抗生素耐药性的增加和新药开发的滞后，单一抗生素在临床感染治疗中的有效性大大降低。广泛耐药（XDR）的革兰氏阴性菌的迅速发展和传播，特别是临床环境中对碳青霉烯类耐药的菌株，加剧了耐药性危机。在这种情况下，抗生素佐剂在振兴现有治疗方法以对抗碳青霉烯耐药细菌感染方面发挥着至关重要的作用。本研究合成了10个小分子抗菌肽模拟物，鉴定出抗菌肽模拟物329 (A329)，该抗菌肽模拟物与米诺环素（FICI = 0.023）具有协同作用，使米诺环素对碳青霉烯耐药肺炎克雷伯菌（CRKP, 0.015≤FICI≤0.141）的抑菌效果显著增强，阻止了米诺环素耐药的出现，提高了小鼠的存活率。8 + 8 mg/kg时，组织细菌负荷降低。机理研究表明，A329增加了细菌膜的通透性，破坏了质子动力。此外，A329与米诺环素联合可促进细胞内米诺环素的积累，诱导细胞内活性氧（ROS）的产生，最终引发细菌死亡。这些发现提示，A329联合米诺环素是一种潜在的联合治疗广泛耐药相关感染的方法。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.