A multi-strategy antimicrobial discovery approach reveals new ways to treat Chlamydia.

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences
PLoS Biology Pub Date : 2025-04-29 eCollection Date: 2025-04-01 DOI:10.1371/journal.pbio.3003123
Magnus Ölander, Daniel Rea Vázquez, Karsten Meier, Aakriti Singh, Amanda Silva de Sousa, Fabiola Puértolas-Balint, Milica Milivojevic, Lieke Mooij, Johanna Fredlund, Eduard Calpe Bosch, María Rayón Díaz, Moa Lundgren, Karin van der Wal, Shaochun Zhu, André Mateus, Bjoern O Schroeder, Jeremy R Lohman, Barbara S Sixt
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引用次数: 0

Abstract

While the excessive use of broad-spectrum antibiotics is a major driver of the global antibiotic resistance crisis, more selective therapies remain unavailable for the majority of bacterial pathogens. This includes the obligate intracellular bacterial pathogens of the genus Chlamydia, which cause millions of urogenital, ocular, and respiratory infections each year. Conducting a comprehensive search of the chemical space for novel antichlamydial activities, we identified over 60 compounds that are chemically diverse, structurally distinct from known antibiotics, non-toxic to human cells, and highly potent in preventing the growth of Chlamydia trachomatis in cell cultures. Some blocked C. trachomatis development reversibly, while others eradicated both established and persistent infections in a bactericidal manner. The top molecules displayed compelling selectivity, yet broad activity against diverse Chlamydia strains and species, including both urogenital and ocular serovars of C. trachomatis, as well as Chlamydia muridarum and Chlamydia caviae. Some compounds also displayed synergies with clinically used antibiotics. Critically, we found the most potent antichlamydial compound to inhibit fatty acid biosynthesis via covalent binding to the active site of Chlamydia FabH, identifying a new mechanism of FabH inhibition and highlighting a possible way to selectively treat Chlamydia infections.

多策略抗菌药物发现方法揭示了治疗衣原体的新方法。
虽然广谱抗生素的过度使用是全球抗生素耐药性危机的主要驱动因素,但大多数细菌病原体仍然无法获得更具选择性的治疗方法。这包括衣原体属的专性细胞内细菌病原体,每年导致数百万例泌尿生殖器、眼部和呼吸道感染。通过对新型抗衣原体活性的化学领域的全面搜索,我们发现了60多种化合物,它们化学成分多样,结构上与已知抗生素不同,对人体细胞无毒,并且在细胞培养中有效地阻止沙眼衣原体的生长。一些药物可逆地阻断了沙眼衣原体的发展,而另一些药物以杀菌的方式根除了既有的和持续的感染。顶部分子显示出令人信服的选择性,但对多种衣原体菌株和物种具有广泛的活性,包括泌尿生殖器和眼部的沙眼衣原体,以及muridarum衣原体和caviae衣原体。一些化合物还显示出与临床使用的抗生素的协同作用。重要的是,我们发现了最有效的抗衣原体化合物,通过与FabH衣原体活性位点的共价结合来抑制脂肪酸的生物合成,确定了FabH抑制的新机制,并强调了选择性治疗衣原体感染的可能方法。
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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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