Tawale Roshan Mukund, Ibrahim Rafwana, Aranjani Jesil Mathew
Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, 576104, Manipal, India.
World J Microbiol Biotechnol. 2025 Aug 26;41(9):317. doi: 10.1007/s11274-025-04512-6.
The current global health issue of antimicrobial resistance necessitates innovative strategies for treating bacterial infections. A promising novel therapeutic target is the multisubunit diguanylate cyclase (DGC), which synthesizes cyclic di-GMP (c-di-GMP) and is implicated in biofilm formation. This multisubunit enzyme regulates critical virulence-associated behaviors in bacteria, such as biofilm formation, motility, and virulence factor synthesis, which are critical for biopathogenicity. This review focuses on the structural and functional characterization of DGCs, their contributions to bacterial pathogenesis, and recent advances in therapies targeting these enzymes. We describe innovations in small-molecule (SM) and peptide-based therapeutics and novel drug delivery platforms that alter DGC activity. In addition, we discuss new findings regarding DGCs and combination therapies of DGC inhibitors with other antibiotics. Finally, we outline the problems and prospects of therapies targeted to DGCs in the clinic. Inhibitors of DGCs may benefit from recent advances in structural biology techniques and medicinal chemistry approaches, which present new drug development opportunities.
当前全球抗菌药物耐药性这一健康问题需要创新的细菌感染治疗策略。一个有前景的新型治疗靶点是多亚基二鸟苷酸环化酶（DGC），它能合成环二鸟苷酸（c-di-GMP）并与生物膜形成有关。这种多亚基酶调节细菌中与毒力相关的关键行为，如生物膜形成、运动性和毒力因子合成，这些对生物致病性至关重要。本综述聚焦于DGC的结构和功能特征、它们对细菌致病机制的作用以及针对这些酶的治疗方法的最新进展。我们描述了小分子（SM）和基于肽的治疗方法以及改变DGC活性的新型药物递送平台方面的创新。此外，我们讨论了关于DGC以及DGC抑制剂与其他抗生素联合治疗的新发现。最后，我们概述了临床上针对DGC治疗的问题和前景。DGC抑制剂可能受益于结构生物学技术和药物化学方法的最新进展，这些进展带来了新的药物开发机会。
