Developing a Gram-Negative Selective Peptide–Drug Conjugate

IF 4.3 3区化学 Q2 CHEMISTRY, MULTIDISCIPLINARY

ACS Omega Pub Date : 2025-08-01 DOI:10.1021/acsomega.4c08000

Thomas N. G. Handley*, Alexandra Brakel, Anthony Maxwell, Jie Ding, Sara Hadjigol, Krijma D’Costa, Chaitra Chandrashekar, Maxwell Alder, Marc-antoine Sani, Graham A. Mackay, Neil O’Brien-Simpson, Ralf Hoffmann, John D. Wade* and Mohammed Akhter Hossain*,

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引用次数: 0

Abstract

Resistance to fluoroquinolone antibiotics has serious implications for healthcare; here, we conjugate the widely used fluoroquinolone ciprofloxacin to a proline-rich antimicrobial peptide (PrAMP) oncocin to improve oncocin’s potency in ciprofloxacin-sensitive and ciprofloxacin-resistant strains of Escherichia coli. The conjugate molecule (oncocin-cipro-c) is ∼3× more potent than the parent oncocin, as determined by MIC, while retaining Gram-negative selectivity. We have characterized oncocin-cipro-c’s interactions with three intracellular targets, two from oncocin (DnaK and 70S ribosome) and a third from ciprofloxacin (gyrase). Oncocin-cipro-c is also able to facilitate mast cell degranulation at a lower concentration than the parent peptide. The development of multimode antibiotics like oncocin-cipro-c is essential in the coming decades of antibiotic resistance.

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革兰氏阴性选择性肽-药物偶联物的研制

对氟喹诺酮类抗生素的耐药性对卫生保健产生严重影响；在这里，我们将广泛使用的氟喹诺酮环丙沙星与富含脯氨酸的抗菌肽（PrAMP）致癌素结合，以提高致癌素对环丙沙星敏感和耐环丙沙星大肠杆菌的效力。通过MIC测定，偶联分子（致癌素-环丙酸-c）比母体致癌素强约3倍，同时保持革兰氏阴性选择性。我们已经确定了癌蛋白-环丙沙星与三个细胞内靶点的相互作用，其中两个来自癌蛋白（DnaK和70S核糖体），第三个来自环丙沙星（gyrase）。在比母体肽浓度更低的情况下，致癌素-环丙酸也能促进肥大细胞脱颗粒。在未来几十年的抗生素耐药问题中，开发多模式抗生素如环丙沙星至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Omega Chemical Engineering-General Chemical Engineering

CiteScore

6.60

自引率

4.90%

发文量

3945

审稿时长

2.4 months

期刊介绍： ACS Omega is an open-access global publication for scientific articles that describe new findings in chemistry and interfacing areas of science, without any perceived evaluation of immediate impact.