Defining principles that influence antimicrobial peptide activity against capsulated <i>Klebsiella pneumoniae</i>.

Abstract

The extracellular polysaccharide capsule of <i>Klebsiella pneumoniae</i> resists 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 encapsulated <i>K. pneumoniae,</i> 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 several <i>K. pneumoniae</i> strains from a previously inactive peptide. We characterized the effects of these two peptides on <i>K. pneumoniae</i>, along with their physical interactions with <i>K. pneumoniae</i> capsule. Both peptides disrupted bacterial cell membranes, but only the active peptide displayed this activity against capsulated <i>K. pneumoniae</i> 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 the <i>K. pneumoniae</i> capsule. Our findings reveal a potential mechanism for disrupting the protective barrier that <i>K. pneumoniae</i> uses to avoid the immune system and last-resort antibiotics.