合成大环内酯克服耐 MLSBK 病原体。

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-07-11 DOI:10.1038/s41421-024-00702-y
Cong-Xuan Ma, Ye Li, Wen-Tian Liu, Yun Li, Fei Zhao, Xiao-Tian Lian, Jing Ding, Si-Meng Liu, Xie-Peng Liu, Bing-Zhi Fan, Li-Yong Liu, Feng Xue, Jian Li, Jue-Ru Zhang, Zhao Xue, Xiao-Tong Pei, Jin-Zhong Lin, Jian-Hua Liang
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引用次数: 0

摘要

传统的大环内酯-林可酰胺-链霉亲和素 B-酮酰胺类(MLSBK)抗生素无法应对因 rRNA 碱基 A2058 构成性甲基化或其 G2058 突变而产生的抗生素耐药性这一日益严峻的挑战,而未修饰 A2058 的存在对于传统 MLSBK 针对病原体而非人体细胞的高选择性至关重要。由于缺乏有效的作用模式,人们更加相信金黄色葡萄球菌对包括泰利霉素在内的现有大环内酯类药物仍然不敏感。在此,我们报告了一系列新型大环内酯类药物的设计和合成,其特点是将酮内酯和喹诺酮分子战略性地融合在一起。通过努力,我们发现了 MCX-219 和 MCX-190 这两种强效化合物,它们对多种可怕的病原体具有更强的抗菌效力,包括 A2058 基因变异的金黄色葡萄球菌、肺炎链球菌、化脓性链球菌,尤其是携带 A2058G 基因突变的临床肺炎支原体分离物,它们与最近在中国爆发的肺炎疫情有牵连。机理研究显示,MCX-190 的修饰喹诺酮分子在新生肽出口隧道内建立了一个独特的二级结合位点。结构-活性关系分析强调了这种二级结合的重要性,这种二级结合通过类似三明治的π-π堆积相互作用和水镁桥来维持,从而有效地与A2058甲基化核糖体而不是喹诺酮类抗生素靶向的拓扑异构酶结合。我们的发现不仅凸显了 MCX-219 和 MCX-190 作为下一代 MLSBK 抗生素的候选药物以对抗抗生素耐药性的前景,还为未来合理设计 MLSBK 类抗生素铺平了道路,为克服抗生素耐药性不断升级所带来的挑战提供了一个战略框架。
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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Synthetic macrolides overcoming MLSBK-resistant pathogens.

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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