Regulation of the VqmA-VqmR quorum-sensing pathway in Vibrio cholerae

Abstract

The global crisis of antibiotic-resistant bacteria demands the search for new alternatives to traditional antibiotics. Bacteria like Vibrio cholerae can form communities in self-produced matrices, called biofilms, that facilitate the sharing and sensing of chemical signals and public goods. Some of the chemical signals are autoinducers that bacteria produce, detect, and collectively respond to in the process called quorum sensing (QS). Through QS, bacteria coordinate the expression of virulence factors and biofilm formation genes. Thus, understanding how V. cholerae regulates its QS-controlled biofilm lifestyle could form the basis for the development of new antibacterial treatments. In V. cholerae, the QS autoinducer 3,5-dimethylpyrazin-2-ol (DPO) binds to and activates the receptor and transcription factor VqmA, which as a complex, activates vqmR expression. VqmR is a small RNA that represses genes required for biofilm formation. Deletion of the threonine dehydrogenase (tdh) gene encoding an enzyme involved in the synthesis of DPO does not fully inhibit vqmR expression, while deletion of the vqmA gene does. This finding suggested that there exist mechanisms of vqmR regulation that are independent of DPO. Mutagenesis and biochemical analyses demonstrate that the absence of phosphotransacetylase (Pta) and the cAMP-receptor protein (CRP) increase expression of vqmR in strains that do not produce DPO. The effect of CRP on vqmR occurs via reduction of VqmA protein levels, while the Pta activity is likely via post-transcriptional regulation of VqmA, which can be rescued by supplementation with acetate or acetyl phosphate. Together, these data provide a connection between the sensing of carbon and acetate availability and QS.