Induction of the Cpx Envelope Stress Pathway Contributes to Escherichia coli Tolerance to Antimicrobial Peptides

Abstract

e Antimicrobial peptides produced by multicellular organisms as part of their innate system of defense against microorganisms are currently considered potential alternatives to conventional antibiotics in case of infection by multiresistant bacteria. However, while the mode of action of antimicrobial peptides is relatively well described, resistance mechanisms potentially induced or selected by these peptides are still poorly understood. In this work, we studied the mechanisms of action and resistance potentially induced by ApoEdpL-W, a new antimicrobial peptide derived from human apolipoprotein E. Investigation of the genetic response of Escherichia coli upon exposure to sublethal concentrations of ApoEdpL-W revealed that this antimicrobial peptide triggers activation of RcsCDB, CpxAR, and E envelope stress pathways. This genetic response is not restricted to ApoEdpL-W, since several other antimicrobial peptides, including polymyxin B, melittin, LL-37, and modified S 4 dermaseptin, also activate several E. coli envelope stress pathways. Finally, we demonstrate that induction of the CpxAR two-component system directly contributes to E. coli tolerance toward ApoEdpL-W, polymyxin B, and melittin. These results therefore show that E. coli senses and responds to different antimicrobial peptides by activation of the CpxAR pathway. While this study further extends the understanding of the array of peptide-induced stress signaling systems, it also provides insight into the contribution of Cpx envelope stress pathway to E. coli tolerance to antimicrobial peptides.

Salmonella enterica Serovar Typhimurium CpxRA Two-Component System Contributes to Gut Colonization in Salmonella-Induced Colitis

“…Antimicrobial peptides activate CpxRA. Some environmental stimuli have been found to activate CpxRA in E. coli (6,(24)(25)(26)(27)(28)(29), including antimicrobial peptides that are constitutively expressed in the gut lumen (28). Therefore, we decided to study whether the S. Typhimurium CpxRA signal transduction system also responds to antimicrobial peptides, stimuli that could be found during gut colonization.…”

“…Some environmental stimuli known to activate CpxRA in E. coli include the overexpression of the outer membrane lipoprotein NlpE (6,24), misfolded P pilin subunits (25), high concentrations of external copper (29), high osmolarity (27,36), antimicrobial cationic polyethylenimine (26), and antimicrobial peptides (28). The osmolarity of the gut lumen is quite high (equivalent to 0.3 M NaCl or higher), and antimicrobial peptides, such as ␣-defensin, are dominantly present (37,38).…”

Vibrio responses to extracytoplasmic stress

“…The mechanism is unknown, however, it is thought that Cpx induces an alternative pathway to rid the cell of toxic metabolites if the RNA efflux pumps are not functional. The Cpx response is also expressed during AMP insults in E. coli (Audrain et al ., ) and Salmonella (Weatherspoon‐Griffin et al ., ) indicating that this function might be conserved across multiple bacterial species.…”

The two‐component system CpxAR is essential for virulence in the phytopathogen bacteria Dickeya dadantii EC3937

“…The CpxAR system regulates expression of genes required for the envelope stress response (Raivio and Silhavy, ) and for motility is required for resistance against antimicrobial peptides (Audrain et al ., ) and is consequently required for virulence (Raivio, 2005; 2014). The Cpx system includes the transmembrane sensor histidine kinase CpxA and its cytoplasmic response regulator CpxR.…”