Cyclic di-GMP (c-di-GMP), a universal second messenger in bacteria, orchestrates a wide array of essential life processes. Its intracellular dynamics are meticulously regulated by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), ensuring precise spatiotemporal control. The functional output of c-di-GMP signaling hinges on effector proteins—molecular decoders that translate c-di-GMP signals into specific cellular responses. This review systematically examines diverse classes of c-di-GMP effectors, using several representative bacterial species as model systems, to dissect their structural and mechanistic diversity. Particular emphasis is placed on their pivotal roles in bacterial pathogenicity, antibiotic tolerance, and host–pathogen interactions, offering fresh insights into the regulatory mechanisms underlying c-di-GMP signaling.

During space flights, opportunistic pathogens carried by astronauts may change their biological characteristics under weightless conditions, potentially affecting the health of astronauts. Simulated microgravity (SMG) has been reported to influence the environmental tolerance, which is related to Escherichia coli ’s environmental tolerance. But the underlying mechanisms remain unclear. Host factor for RNA phage Q _β replicase ( hfq ) is an RNA molecular chaperone protein found in bacteria. In this study, we discovered that hfq expression in E. coli increases under SMG through transcriptome sequencing analysis. We knocked out hfq in E. coli to establish a Δhfq – E. coli strain to investigate the effect of hfq on the environmental tolerance of E. coli under SMG, and observed changes in Coproporphyrinogen III dehydrogenase ( hemN ) and RNA polymerase sigma factor ( rpoS ), which are related to the environmental tolerance of E. coli . Results showed that the growth level of Δhfq – E. coli was significantly lower than that of the wild‐type strain under SMG. E. coli enhances its tolerance to oxidative stress through the hfq – hemN pathway under SMG. After SMG exposure, E. coli ’s tolerance to high temperatures and acidic environments changed, but these changes were not mediated by the hfq – rpoS pathway; instead, they may act synergistically. This study provides a foundation for preventing and controlling opportunistic pathogenic bacterial infections during aerospace missions.