Updates on therapeutic targeting of diguanylate cyclase for addressing bacterial infections: A comprehensive review

Abstract

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.