UC Irvine

To combat the growing threat of antibiotic resistance, new antimicrobial strategies are urgently needed. Here, I describe a strategy and mechanism that combines antimicrobial peptides (AMPs) with histones, which can be used to treat pathogenic Pseudomonas aeruginosa and Staphylococcus aureus bacteria, and Aspergillus fumigatus fungi. When combined in Gram-negative bacteria, AMPs target the outer membranes of bacteria and enable histones to pass the lipopolysaccharide-rich outer membrane. Here, histones can increase the number and size of membrane pores by targeting bacterial membranes that have significantly less lipopolysaccharide, including the bacterial inner membrane and inner leaflet of the outer membrane, and contribute to bacterial membrane damage from the inside. Consistent with this, histones increase the efficacy of the antibiotic and AMP polymyxin B to treat P. aeruginosa. Altogether, this strategy of combining histones with antimicrobial peptides is an effective alternative antimicrobial mechanism against Gram-negative bacteria and can also be extended to clinically-relevant Gram-positive bacteria and fungi. This research can be used to improve the efficacy of current antimicrobials and guide the development of novel antibiotic strategies against various microbes.