Defining principles that influence antimicrobial peptide activity against capsulatedKlebsiella pneumoniae

Abstract

The extracellular polysaccharide capsule ofKlebsiella pneumoniaeresists penetration by antimicrobials and protects the bacteria from the innate immune system. Host antimicrobial peptides are inactivated by the capsule as it impedes their penetration to the bacterial membrane. While the capsule sequesters most peptides, a few antimicrobial peptides have been identified that retain activity against encapsulatedK. pneumoniae,suggesting that this bacterial defense can be overcome. However, it is unclear what factors allow peptides to avoid capsule inhibition. To address this, we created a peptide analog with strong antimicrobial activity toward severalK. pneumoniaestrains from a previously inactive peptide. We characterized the effects of these two peptides onK. pneumoniae, along with their physical interactions withK. pneumoniaecapsule. Both peptides disrupted bacterial cell membranes, but only the active peptide displayed this activity against capsulatedK. pneumoniae. Unexpectedly, the active peptide showed no decrease in capsule binding, but did lose secondary structure in a capsule-dependent fashion compared with the inactive parent peptide. We found that these characteristics are associated with capsule-peptide aggregation, leading to disruption of theK. pneumoniaecapsule. Our findings reveal a potential mechanism for disrupting the protective barrier thatK. pneumoniaeuses to avoid the immune system and last-resort antibiotics.