Glycodiversification of gentamicins through in vivo glycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity

IF 14.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI:10.1016/j.apsb.2024.04.030
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Abstract

Aminoglycosides (AGs) are a class of antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs, therefore referred to as genkamicins (GKs). The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.

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通过体内糖基转移酶交换实现庆大霉素的糖基化,从而创造出具有强效活性和低耳毒性的新型混合氨基糖苷类抗生素
氨基糖苷类(AGs)是一类具有广谱活性的抗生素。然而,由于与肾毒性和耳毒性相关的安全性问题以及耐药性,它们的使用受到了限制。为了解决这些问题,对天然 AGs 进行修饰的半合成方法产生了新一代 AGs,但由于合成方面的巨大挑战,修饰类型有限。本研究探索了一种新方法,即利用庆大霉素和卡那霉素的细菌生物合成机制来制造杂交 AGs。这是通过将庆大霉素生产者中的糖基转移酶(GT)与卡那霉素生物合成途径中的糖基转移酶(GT)进行糖基化来实现的,结果产生了一系列新型 AGs,因此被称为基因激肽(GKs)。通过对混合代谢途径的操作,成功地积累了不同种类的 GK,并分离和鉴定了六种 GK 成分。这些化合物对世界卫生组织(WHO)关键优先病原体的抗菌活性保持不变,尤其是 GK-C2a,与斑马鱼胚胎中的临床药物相比,具有较低的耳毒性。这项研究为AGs结构的多样化提供了一种新策略,也为开发毒性较低的AG药物防治传染病提供了一条潜在的途径。
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来源期刊
Acta Pharmaceutica Sinica. B
Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
22.40
自引率
5.50%
发文量
1051
审稿时长
19 weeks
期刊介绍: The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.
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