Grant: Project Grant

Pseudomonas aeruginosa is notorious for causing various infections in immunocompromised individuals. Particularly in cystic fibrosis patients, it is the major cause of lung infection and is responsible for chronic infection in up to 85% of the patients. Resistance of P. aeruginosa to multiple antibiotics makes the eradication of infections a challenge. Although P. aeruginosa uses various mechanisms to resist the action of antibiotics, energy-dependent efflux of antibiotics, using the so-called RND pumps, is one of the key mechanisms. Using this mechanism, P. aeruginosa pumps out the antibiotic molecule to the external environment and therefore prevents the antibiotic molecules from reaching an effective concentration within the bacterial cell. The functional RND complex is formed by three different proteins. Our goal is to understand the mechanisms by which these three proteins interact. In this application we propose to study the mechanisms of interaction between different components of multidrug resistance efflux pumps belonging to the RND family in P. aeruginosa. Previous work from our and our collaborator's laboratory shows that one of the three components of the RND complex that is present in the bacterial outer membrane may play a role in determining which antibiotic is recognized by the complex. This is a novel finding that has not been shown before. This finding may also lead towards new avenues of investigation that may lead to the inhibition of RND complexes, however this requires more in-depth study of the mechanisms of interaction between the RND complex components. We have developed a number of state-of-the-art genetic tools for P. aeruginosa that will aid in studying the mechanisms of interaction between different components of the RND complex. Since antibiotic resistance of P. aeruginosa is a major hurdle in eradication of infections, knowledge generated from the proposed work will assist in finding new ways to treat P. aeruginosa infections.