Chemical biology strategies for delineating the role of inter-species cell-cell communication in bacterial co-infections with Pseudomonas aeruginosa and the Burkholderia cepacia complex

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PROJECT SUMMARY Polymicrobial infections are a common and devastating feature of many lung diseases, including those associated with cystic fibrosis (CF). The opportunistic pathogen, Pseudomonas aeruginosa, infects ~50% of CF patients, and a significant number of these patients are subsequently co-infected with members of the Burkholderia cepacia complex (Bcc), a group of 17 closely-related Burkholderia species.1,2 These species form co-biofilms in the CF lung,3 which are associated with rapid decline in pulmonary function. The intrinsic and evolved antibiotic resistance of these bacteria within these co-biofilms make for very limited treatment options. Recently, antivirulence strategies—i.e., therapies that render bacteria avirulent without targeting essential cellular processes—have attracted considerable interest as a strategy to address bacterial pathogenicity without applying selective pressure.4,5 Both P. aeruginosa and Burkholderia species coordinate virulence phenotypes and biofilm production by deploying acyl homoserine lactone (AHL) signals for cell-to-cell communication (or quorum sensing (QS)). Moreover, they appear to be more virulent in co-infections as opposed to alone, suggesting that there may be interspecies interactions that facilitate this enhancement. Manipulation of QS pathways has emerged as one potentially powerful antivirulence strategy and is a primary research focus of the Blackwell lab.6-8 We hypothesize that QS plays a role in augmenting virulence in P. aeruginosa:Bcc co-infections. The broad goal of this project is to test this hypothesis through an integrated set of modern chemical biology, organic chemistry, microbiology, and molecular biology approaches. Despite the advances in developing synthetic QS modulators for P. aeruginosa, minimal work has been focused on identifying compounds that target QS in Burkholderia species. In Aim 1, I will identify and synthesize novel chemical modulators of QS for the Bcc, confirm their ability to modify virulence phenotypes, and evaluate their ability to attenuate C. elegans infections. These compounds will represent powerful tools to explore the role of QS in infection, and we believe they could provide new entry into study of the role of QS in co-infections, such as those in the CF lung. In Aims 2 and 3, I will assess the ability for P. aeruginosa to co-biofilm and co-infect C. elegans with range of Bcc member species. Furthermore, I will dissect the role of QS in these co-infections using species-specific chemical tools. Finally, I will challenge compound-treated co-infections with antibiotics, to evaluate if our best QS modulators render the co-infections or co-biofilms more susceptible to antibiotic treatment. The results of the proposed experiments will be highly impactful and novel as they will assess of the role of QS in co-infections between these two destructive pathogens for the first time, and they will further the use of antivirulence strategies as an innovative way to treat infection.