Carolyn L. Cannon, M.D., Ph.D.

DEPARTMENT OF Pediatrics
Keywords: bacterial pathogenesis, drug mechanisms, drug resistance, host-parasite interaction, metals, nanotechnology

Our studies address the pathogenesis of pulmonary infection with several related bacterial species found in the lungs of patients with cystic fibrosis (CF) and development of novel therapies to treat these infections. Using both in vitro and mouse models of infection, we explore the role that CFTR plays in clearance of Pseudomonas aeruginosa and Burkholderia cepacia complex (Bcc) organisms. Clearance of P. aeruginosa depends on internalization of the bacteria followed by apoptosis of the epithelial cell. Failure of mutant CFTR to cluster into lipid rafts after interacting with P. aeruginosa LPS leads to decreased internalization of the bacteria, decreased apoptosis of the host cell and ultimately, increased lung burden of the bacteria. Clearance of Bcc organisms is less well understood, in part, because these species are highly antibiotic resistant complicating manipulation in the laboratory. However, a series of novel silver-based antimicrobials, silver N-heterocyclic carbene complexes, inhibit the growth of all bacterial species tested to date including the CF lung pathogens P. aeruginosa and Bcc organisms. Silver complexes are currently used as antimicrobials to treat Staphylococcus aureus and P. aeruginosa infections in burn patients and have a long history of safe use for these topical applications. The use of silver compounds to treat pulmonary infections, however, has not yet been fully explored. Silver carbene complexes (SCCs) are water soluble, and hence amenable to nebulization for drug delivery and many complexes may be incorporated into nanoparticles for nebulized delivery of long-acting, broad-spectrum antibiotics. Using our mouse infection models, we have demonstrated efficacy of nebulized (SCCs), formulated both as a solution and after incorporation into nanoparticles. We are now exploring the role that metal transporters in both bacteria and in respiratory epithelial cells (ATP7A or Menkes protein, ATP7B or Wilson protein) might serve to detoxify the cells leading to decreased sensitivity to silver.