Effect of PhoP-PhoQ Activation by Broad Repertoire of Antimicrobial Peptides on Bacterial Resistance

Abstract

Pathogenic bacteria can resist their microenvironment by changing the expression of virulence genes. In Salmonella typhimurium, some of these genes are controlled by the two-component system PhoP-PhoQ. Studies have shown that activation of the system by cationic antimicrobial peptides (AMPs) results, among other changes, in outer membrane remodeling. However, it is not fully clear what characteristics of AMPs are required to activate the PhoP-PhoQ system and whether activation can induce resistance to the various AMPs. For that purpose, we investigated the ability of a broad repertoire of AMPs to traverse the inner membrane, to activate the PhoP-PhoQ system, and to induce bacterial resistance. The AMPs differ in length, composition, and net positive charge, and the tested bacteria include two wild-type (WT) Salmonella strains and their corresponding PhoP-PhoQ knock-out mutants. A lacZ-reporting system was adapted to follow PhoP-PhoQ activation. The data revealed that: (i) a good correlation exists among the extent of the positive charge, hydrophobicity, and amphipathicity of an AMP and its potency to activate PhoP-PhoQ; (ii) a ؉1 charged peptide containing histidines was highly potent, suggesting the existence of an additional mechanism independent of the peptide charge; (iii) the WT bacteria are more resistant to AMPs that are potent activators of PhoP-PhoQ; (iv) only a subset of AMPs, independent of their potency to activate the system, is more toxic to the mutated bacteria compared with the WT strains; and (v) short term exposure of WT bacteria to these AMPs does not enhance resistance. Overall, this study advances our understanding of the molecular mechanism by which AMPs activate PhoP-PhoQ and induce bacterial resistance. It also reveals that some AMPs can overcome such a resistance mechanism.

Bcr1 Functions Downstream of Ssd1 To Mediate Antimicrobial Peptide Resistance in Candida albicans

“…For example, a P. aeruginosa mutant that lacks the transcriptional regulator PsrA is defective in biofilm formation and has increased susceptibility to the bovine neutrophil antimicrobial peptide indolicidin (27). Moreover, PhoQ, which is a member of a two-component regulatory system, governs both biofilm formation and antimicrobial peptide resistance in P. aeruginosa and Salmonella enterica serovar Typhimurium (28)(29)(30). Based on the link between biofilm formation and antimicrobial peptide resistance in organisms from two different phyla, it seems probable that both processes depend on factors that influence the cell wall and cell surface.…”

Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection

“…Polymorphonuclear cells also contain numerous classes of antimicrobial peptides within cytoplasmic granules (68,69). PhoP and PhoQ comprise a two-component regulatory system that responds to antimicrobial peptides to regulate genes for LPS biosynthesis and virulence (43,(70)(71)(72)(73).…”

Defensive remodeling: How bacterial surface properties and biofilm formation promote resistance to antimicrobial peptides

“…Mutants in the pmrC of S. enterica Typhimurium and in lptA of N. gonorrhoeae were more 15 sensitive to PmB compared to the WT [105]. In addition, an in vivo study with N. gonorrhoeae…”

“…It is believed that the chemical and physical characteristics of AMPs such as a positive net charge secondary structure and amphipathic nature are important for their antimicrobial activity [6, [14][15][16]. For example, in the case of Gram-negative bacteria, due to their net positive charge, AMPs have high affinity to the negatively charged LPS, and then can displace divalent cations that are naturally bound to it.…”