Elucidating the mechanism by which synthetic helper peptides sensitize Pseudomonas aeruginosa to multiple antibiotics.
Yushan XiaRubén CebriánCongjuan XuAnne de JongWeihui WuOscar Paul KuipersPublished in: PLoS pathogens (2021)
The emergence and rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to the global healthcare. There is an urgent need for new antibacterial substances or new treatment strategies to deal with the infections by MDR bacterial pathogens, especially the Gram-negative pathogens. In this study, we show that a number of synthetic cationic peptides display strong synergistic antimicrobial effects with multiple antibiotics against the Gram-negative pathogen Pseudomonas aeruginosa. We found that an all-D amino acid containing peptide called D-11 increases membrane permeability by attaching to LPS and membrane phospholipids, thereby facilitating the uptake of antibiotics. Subsequently, the peptide can dissipate the proton motive force (PMF) (reducing ATP production and inhibiting the activity of efflux pumps), impairs the respiration chain, promotes the production of reactive oxygen species (ROS) in bacterial cells and induces intracellular antibiotics accumulation, ultimately resulting in cell death. By using a P. aeruginosa abscess infection model, we demonstrate enhanced therapeutic efficacies of the combination of D-11 with various antibiotics. In addition, we found that the combination of D-11 and azithromycin enhanced the inhibition of biofilm formation and the elimination of established biofilms. Our study provides a realistic treatment option for combining close-to-nature synthetic peptide adjuvants with existing antibiotics to combat infections caused by P. aeruginosa.
Keyphrases
- gram negative
- multidrug resistant
- drug resistant
- pseudomonas aeruginosa
- acinetobacter baumannii
- biofilm formation
- reactive oxygen species
- cell death
- amino acid
- candida albicans
- healthcare
- staphylococcus aureus
- cystic fibrosis
- cell cycle arrest
- induced apoptosis
- dna damage
- escherichia coli
- oxidative stress
- dendritic cells
- drug delivery
- fatty acid
- inflammatory response
- endothelial cells
- cell proliferation
- endoplasmic reticulum stress
- health insurance
- health information
- quantum dots
- drinking water
- sensitive detection