Investigation of capsule interactions that promote antimicrobial peptide activity

Project Summary. The extracellular polysaccharide capsule of Klebsiella pneumoniae resists penetration by antimicrobials and protects the bacteria from the innate immune system. While capsule inhibits most host defense peptides and polymyxin antibiotics, a few amphipathic antimicrobial peptides have been identified that retain activity against capsulated K. pneumoniae. However, it is not known what enables some peptides to avoid sequestration by K. pneumoniae capsule while it effectively neutralizes most others. We have uncovered a mechanism that allows synthetic antimicrobial peptides to overcome capsule inhibition. Specific amino acid changes in inactive sequences enable peptides to bind, aggregate, and disrupt capsule layers, leaving K. peumoniae vulnerable to their membrane attack. Through this proposal we will 1) explore this new mechanism in innate immune host defense peptides that kill capsulated K. pneumoniae, and 2) characterize amino acid sequence and positional variations that promote activity towards capsulated bacteria. Our results will provide important insight into immune evasion by K. pneumoniae and other capsulated bacteria, and identify mechanistic principles will aid the development new therapeutic approaches to overcome the capsule barrier.