Enhancing the Potency of Nalidixic Acid toward a Bacterial DNA Gyrase with Conjugated Peptides,ACS Chemical Biology

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Enhancing the Potency of Nalidixic Acid toward a Bacterial DNA Gyrase with Conjugated Peptides
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-09-01 00:00:00 , DOI: 10.1021/acschembio.7b00540
Marya Ahmed ₁ , Shana O. Kelley ₁

Affiliation

Quinolones and fluoroquinolones are widely used antibacterial agents. Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide–nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate—featuring a peptide containing cyclohexylalanine and arginine—exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide–NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.

中文翻译：

增强萘啶酸对带有共轭肽的细菌DNA旋转酶的效力

喹诺酮和氟喹诺酮是广泛使用的抗菌剂。萘啶酸（NA）是第一代基于喹诺酮的抗生素，具有较窄的光谱和较差的药代动力学。在这里，我们描述了一系列由固相肽合成制备的具有不同水平的疏水性和分子电荷的肽-萘啶酸共轭物，它们在效能上表现出令人着迷的改善。与在金黄色葡萄球菌中具有低水平效力的NA相比，具有优化的疏水性和分子电荷的NA肽缀合物显示出显着改善的抗菌活性。最有效的NA缀合物（具有包含环己基丙氨酸和精氨酸的肽）可有效吸收细菌，特别是对金黄色葡萄球菌具有特异性抑制作用DNA促旋酶。对肽-NA共轭物的系统研究表明，要克服金黄色葡萄球菌DNA促旋酶对这种喹诺酮类药物的内在抗性，需要在锚定于药物核心的附件中实现阳离子电荷和疏水性的良好平衡。

更新日期：2017-09-04

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