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Peptide 1018 inhibits swarming motility and dysregulates transcriptional regulators of swarming in Pseudomonas aeruginosa Wilkinson, Lauren Valerie

Abstract

Pseudomonas aeruginosa is a Gram-negative environmental pathogen responsible for considerable human morbidity and mortality, especially in vulnerable hospital populations and individuals with cystic fibrosis. Much of this impact stems from its enormous capacity to adapt, colonize, and thrive in a broad variety of host and environmental niches. In P. aeruginosa, adaptive behaviours like biofilm formation and swarming motility can confer significant but conditionally reversible multiple antibiotic resistance, and considerably reduce the efficacy of many clinical antibiotics. Swarming motility is a transitory adaptive behaviour that is induced under stringent conditions (e.g., nutrient limitation, medium viscosity) and has been linked to both in vivo virulence and acute infection in P. aeruginosa. A small, synthetic host defense peptide, 1018, with weak bactericidal activity inhibits the adaptive behaviour biofilm formation at low concentrations in a broad spectrum of Gram-negative and Gram-positive pathogenic bacteria. It also shows synergy with a number of conventional antibiotics. This study aimed to investigate the effect of this peptide on swarming motility. Peptide 1018 inhibited swarming motility at low concentrations in P. aeruginosa and disrupted the expression of seventy-four regulatory genes, including ten of the thirty-five genes identified as swarming regulators. Peptide treatment of bacteria also induced a gene expression profile with significant similarity (67.7%) to cells with a stationary, biofilm-like phenotype. A moderate number of P. aeruginosa mutants with single gene interruptions showed weak tolerance to peptide 1018, and the majority of these interrupted genes were linked to adaptation and survival under stringent conditions. The tolerance phenotype associated with two of these genes, rhlB and anr, was confirmed by complementation. Enhancing the bacterial stringent response through induced amino acid starvation appeared to improve the tolerance of P. aeruginosa to peptide 1018 in a swarming environment. Under these conditions, the wild-type strain and the peptide-tolerant mutants showed respective rescued and enhanced swarming motility when treated with peptide 1018. This study thus supports a link between the mechanism of action of peptide 1018 and the stringent response and demonstrates that peptide 1018 inhibits and broadly dysregulates swarming motility, an adaptive behaviour promoting enhanced antibiotic resistance.

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