Targeting Bacterial Second Messenger c‑di‑GMP: Exploring the Potential of Non‑Bactericidal Anti‑Infective Agents

A review published in Annual Review of Microbiology notes that cyclic‑di‑GMP (c‑di‑GMP), a widespread bacterial second messenger, regulates bacterial motility, biofilm formation and virulence secretion systems. It profoundly modulates host colonization by both pathogenic and commensal bacteria in animals and plants, offering novel targets for anti‑biofilm and anti‑infective drug development.

c‑di‑GMP is synthesized by diguanylate cyclases (DGCs) and degraded by phosphodiesterases (PDEs). Although numerous signaling pathways have been characterized in vitro, c‑di‑GMP signaling inside host organisms often differs from in‑vitro observations. For pathogens such as Vibrio cholerae, as well as beneficial symbionts including rhizobia and Vibrio fischeri, host microenvironments reshape c‑di‑GMP levels. Excess c‑di‑GMP frequently impairs bacterial colonization efficiency within hosts.

Major knowledge gaps remain in this field. Many bacterial species encode dozens of DGC/PDE proteins. The host‑derived signals sensed in‑vivo and regulatory mechanisms of dual‑domain proteins are poorly understood. Functions of c‑di‑GMP among commensal gut microbiota also remain under‑studied.

Industry insiders point out that targeting the c‑di‑GMP pathway suppresses biofilm formation and bacterial virulence instead of directly killing bacteria, which may ease the pressure of antibiotic resistance. Limited by the lack of in‑vivo detection tools, further host‑relevant in‑situ experiments are required to advance c‑di‑GMP‑targeted molecules toward anti‑infective lead‑compound development.

FOR DETAIL:  https://doi.org/10.1146/annurev-micro-041522-101729

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