When Dr. Cardona started research in Bcc’s pathogenomics, she discovered that the taxonomy of Bcc could not predict virulence (Cardona et al., 2005) and decided to investigate other factors. At that time, bacterial metabolism was not recognized as a virulence factor; however, we discovered that the phenylacetic acid (PAA) degradation pathway was necessary for full virulence of Bcc (Law et., al, 2008). Dr. Cardona’s laboratory laid the groundwork for the relationship between PAA and virulence when they discovered the molecular basis of the attenuation phenotype in a PAA-CoA ring hydroxylation mutant (ΔpaaABCDE) that regulates quorum sensing-related virulence (Privytkova et al., 2014). We recently demonstrated that there is an indirect connection between PAA-CoA and quorum sensing regulation in B. cenocepacia (Lightly et al., 2019)
Our data suggest that PAA-CoA acts as a co-repressor, with an as yet unidentified transcriptional regulator (XR). In wild type CepIR QS dominates the regulation of virulence due to the lower concentration of PAA-CoA (top left panel). Whereas in ∆paaABCDE the levels of PAA-CoA are high and the XR:PAA-CoA complex can compete with CepR:C8-HSL complexes to repress virulence, resulting in an attenuated virulence compared to wild type (top right panel). CepR mutants in wild type do not have CepR:C8-HSL complexes to regulate virulence and are therefore attenuated for virulence (bottom panel). However, in a PaaK background CepR mutants are virulent. The absence of PAA-CoA in these mutants in combination with the lack of CepR create the perfect conditions for XR to positively regulate virulence genes. Using transposon mutagenesis, we are working to identify this missing piece of our puzzle.
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