Biofilms are communities of microorganisms that live in a self-produced extracellular matrix in order to survive in hostile environments. Second messengers, such as c-di-GMP and cAMP, participate in the regulation of biofilm formation. c-di-GMP is a major molecule that is involved in modulating the bacterial transition between a planktonic lifestyle and biofilm formation. Aside from regulating carbon catabolism repression in most bacteria, cAMP has also been found to mediate biofilm formation in many bacteria. Although the underlying mechanisms of biofilm formation mediated by cAMP-CRP have been well-investigated in several bacteria, the regulatory pathways of cAMP-CRP are still poorly understood compared to those of c-di-GMP. Moreover, some bacteria appear to form biofilm in response to changes in carbon source type or concentration. However, the relationship between the carbon metabolisms and biofilm formation remains unclear. This mini-review provides an overview of the cAMP-CRP-regulated pathways involved in biofilm formation in some bacteria. This information will benefit future investigations of the underlying mechanisms that connect between biofilm formation with nutrient metabolism, as well as the cross-regulation between multiple second messengers.

Biofilms are multicellular communities of microbes that are encased within an extracellular matrix. Environmental factors induce bacteria to form biofilm. Bacteria have several regulatory mechanisms in response to environmental changes, and the two-component signal transduction system (TCS) is a major strategy in connecting changes in input signals to changes in cellular physiological output. The TCS employs multiple mechanisms such as cross-regulation, to integrate and coordinate various input stimuli to control biofilm formation. In this mini-review, we demonstrate the roles of TCS on biofilm formation, illustrating these input signals and modulation modes, which may be utilized by future investigations in elucidating the regulatory signals and underlying the mechanisms of biofilm formation.

Nucleotide second messengers, such as cAMP and c-di-GMP, regulate many physiological processes in bacteria, including biofilm formation. There is evidence of cross-talk between pathways mediated by c-di-GMP and those mediated by the cAMP receptor protein (CRP), but the mechanisms are often unclear. Here, we show that cAMP-CRP modulates biofilm maintenance in Shewanella putrefaciens not only via its known effects on gene transcription, but also through direct interaction with a putative c-di-GMP effector on the inner membrane, BpfD. Binding of cAMP-CRP to BpfD enhances the known interaction of BpfD with protease BpfG, which prevents proteolytic processing and release of a cell surface-associated adhesin, BpfA, thus contributing to biofilm maintenance. Our results provide evidence of cross-talk between cAMP and c-di-GMP pathways through direct interaction of their effectors, and indicate that cAMP-CRP can play regulatory roles at the post-translational level.