Antimicrobial and antibiofilm activity of human recombinant H1 histones against bacterial infections

Abstract

AbstractHistones possess significant antimicrobial potential, yet their activity against biofilms remains underexplored. Moreover, concerns regarding adverse effects limit their clinical implementation. We investigated the antibacterial efficacy of human recombinant histone H1 subtypes againstPseudomonas aeruginosaPAO1, both planktonic and in biofilms. After thein vitrotests, toxicity and efficacy were assessed in aP. aeruginosaPAO1 infection model usingGalleria mellonellalarvae. Histones were also evaluated in combination with ciprofloxacin and gentamicin. Our results demonstrate antimicrobial activity against of all three histones againstP. aeruginosaPAO1, with H1.0 and H1.4 showing efficacy at lower concentrations. The bactericidal effect was associated with a mechanism of membrane disruption.In vitrostudies using static and dynamic models showed that H1.4 had antibiofilm potential by reducing cell biomass. Neither H1.0 nor H1.4 showed toxicity inG. mellonellalarvae, and both increased larvae survival when infected withP. aeruginosaPAO1. Althoughin vitrosynergism was observed between ciprofloxacin and H1.0, no improvement over the antibiotic alone was notedin vivo. Differences in antibacterial and antibiofilm activity were attributed to sequence and structural variations among histone subtypes. Moreover, the efficacy of H1.0 and H1.4 was influenced by the presence and strength of the extracellular matrix. These findings suggest histones hold promise for combating acute and chronic infections caused by pathogens such asP. aeruginosa.ImportanceThe constant increase of multidrug-resistant bacteria is a critical global concern. The inefficacy of current therapies to treat bacterial infections is attributed to multiple mechanisms of resistance, including the capacity to form biofilms. Therefore, the identification of novel and safe therapeutic strategies is imperative. This study confirms the antimicrobial potential of three histone H1 subtypes against both Gram-negative and Gram-positive bacteria. Furthermore, histones H1.0 and H1.4 demonstratedin vivoefficacy without associated toxicity in an acute infection model ofPseudomonas aeruginosaPAO1 inGalleria mellonellalarvae. The bactericidal effect of these proteins also resulted in reduction in biomass ofP. aeruginosaPAO1 biofilms. Given the clinical significance of this opportunistic pathogen, our research provides a comprehensive initial evaluation of the efficacy, toxicity, and mechanism of action of a potential new therapeutic approach against acute and chronic bacterial infections.