Summit Therapeutics, Cambridge, United Kingdom.
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA.
Antimicrob Agents Chemother. 2023 May 17;67(5):e0156322. doi: 10.1128/aac.01563-22. Epub 2023 Apr 24.
Clostridioides difficile infection (CDI) causes substantial morbidity and mortality worldwide with limited antibiotic treatment options. Ridinilazole is a precision bisbenzimidazole antibiotic being developed to treat CDI and reduce unacceptably high rates of infection recurrence in patients. Although in late clinical development, the precise mechanism of action by which ridinilazole elicits its bactericidal activity has remained elusive. Here, we present conclusive biochemical and structural data to demonstrate that ridinilazole has a primary DNA binding mechanism, with a co-complex structure confirming binding to the DNA minor groove. Additional RNA-seq data indicated early pleiotropic changes to transcription, with broad effects on multiple C. difficile compartments and significant effects on energy generation pathways particularly. DNA binding and genomic localization was confirmed through confocal microscopy utilizing the intrinsic fluorescence of ridinilazole upon DNA binding. As such, ridinilazole has the potential to be the first antibiotic approved with a DNA minor groove binding mechanism of action.
艰难梭菌感染（CDI）在全球范围内导致了大量的发病率和死亡率，抗生素治疗选择有限。利奈唑胺是一种正在开发用于治疗 CDI 并降低患者感染复发率的精准双苯并咪唑抗生素。尽管处于后期临床开发阶段，但利奈唑胺发挥杀菌活性的确切作用机制仍难以捉摸。在这里，我们提供了确凿的生化和结构数据，证明利奈唑胺具有主要的 DNA 结合机制，共复合物结构证实与 DNA 小沟结合。额外的 RNA-seq 数据表明转录的早期多效性变化，对多种艰难梭菌隔室有广泛影响，特别是对能量生成途径有重大影响。通过利用利奈唑胺结合 DNA 时的固有荧光，通过共聚焦显微镜证实了 DNA 结合和基因组定位。因此，利奈唑胺有可能成为第一个批准具有 DNA 小沟结合作用机制的抗生素。
