Functionality of CdrA and its processed forms within Pseudomonas aeruginosa biofilms

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PROJECT SUMMARY/ABSTRACT Microbial communities called biofilms are hallmarks of chronic infections. Pseudomonas aeruginosa is a model for biofilm study, and also is a pathogen that causes biofilm infections including of burns, wounds, urinary catheters, contact lenses, and the airways of patients with cystic fibrosis (CF). Biofilm microbes are encased in a mesh-like extracellular matrix that helps bacteria to evade host defenses and protects against external assaults such as antimicrobial treatment. A better understanding of biofilm matrix assembly is necessary to improve prevention and treatment of biofilm-involved infections. The long-term goal of this application and the candidate, Dr. Reichhardt, is to establish an independent research program focused on the nature and functional impact of intermolecular interactions in biofilm. Towards this goal, the immediate career objective of Dr. Reichhardt is to obtain an independent faculty position using the proposed research as the foundation of her job applications. The overall research objective of this application is to investigate the flexibility and control of matrix interactions of the key P. aeruginosa protein CdrA. Based on preliminary data, the hypothesis is that the biofilm functionality of CdrA can be expanded through enzymatic processing and binding to host factors, impacting biofilm stability. To test this hypothesis, two specific aims are proposed and will be investigated using Dr. Reichhardt’s unique multidisciplinary training in biophysical chemistry and microbiology. Aim 1 will elucidate the biofilm functionality of CdrA and its processed forms within P. aeruginosa biofilms including those found in chronic infections. Aim 2 will examine the ability of CdrA to integrate host material into biofilms and determine if these host factor- integrated biofilms are more protected against antimicrobials and host immune responses. These aims are expected to transform the established view of biofilm matrices as static structures that are formed by only self- produced biomolecules. This improved understanding will advance biofilm microbiology and aid the creation of effective treatments for chronic infections. This proposal includes a career development plan to complement Dr. Reichhardt’s prior experience so that she can successfully transition to an independent research faculty position. Dr. Reichhardt has assembled a multidisciplinary mentorship committee to help her achieve her scientific and career development goals. Professor Parsek is an ideal mentor for Dr. Reichhardt since he is internationally recognized as a leader in biofilm microbiology, and he has a strong track record producing successful independent academic scientists, including several with multidisciplinary backgrounds. The proposed research is distinct from that of Professor Parsek, and the results of this project will transition with Dr. Reichhardt to her future independent research program. Additionally, results generated from the proposed research aims are expected to help Dr. Reichhardt successfully compete for R01 funding.