Abstract
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.
Highlights
The development of multi-drug resistance is a global phenomenon that severely impairs the effectiveness of antibacterial chemotherapy
This is especially critical for Gram-negative bacteria, which remain the most problematic group, because, among other reasons, the outer membrane acts as a permeability barrier preventing antibiotics to reach their targets
P. aeruginosa exhibits strong tolerance to azithromycin in vitro, it is still the clinically recommended antibiotic for the treatment of P. aeruginosa infections in vivo especially in cystic fibrosis patients (CF) patients [19,20], since, at sub-MIC concentrations, azithromycin retards biofilm formation of P. aeruginosa [21] and it has shown anti-inflammatory and anti-virulence properties [22]
Summary
The development of multi-drug resistance is a global phenomenon that severely impairs the effectiveness of antibacterial chemotherapy. Only a few new narrowspectrum drugs have been developed, while the existing drugs are rapidly losing their efficacy [1,2]. Gram-negative bacteria remain the most challenging group since the outer membrane acts as a permeability barrier, which makes difficult for antibiotics to reach their intracellular targets [5]. For this reason, it is not surprising that P. aeruginosa has been pointed out as one of the most problematic Gram-negative pathogens for which new treatments are urgently needed. The extracellular matrix of biofilms shields the bacteria from antibiotics, making the embedded bacteria up to 1,000 times more resistant [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
