Killing of colistin-resistant Aeromonas hydrophila by a synthetic peptide

Multi-drug-resistant Aeromonas hydrophila infections are becoming increasingly threatening, and the development of novel antimicrobial drugs is indispensable. Herein, we demonstrate that this novel peptide is highly active against colistin-resistant A. hydrophila strain and shows sustained killing efficacy in vivo. Mechanistic studies showed that D-Q7 interacted with phosphatidylglycerol and lipopolysaccharide in the bacterial cell membrane, with an increase in intracellular ROS as well as a decrease in ATP level, ultimately leading to cell membrane disruption and bacterial death. Importantly, our study identified gene3832 as a potential regulator of membrane permeability, which may act as a potential modulator of bacterial susceptibility to D-Q7. The role of gene3832 was further confirmed by gene knockout and complementation assays. Consistently, we observed that gene3832 was also involved in biofilm formation in the colistin-resistant A. hydrophila strain. Collectively, our study provides an effective antimicrobial strategy with potential targets for the treatment of drug-resistant A. hydrophila infection.IMPORTANCEAs an environmental, zoonotic pathogen, Aeromonas hydrophila remains a major pathogenic bacterium, bringing large economic losses and eco-environmental pressure during the event of large-scale infection. Currently, the occurrence of colistin-resistant A. hydrophila poses a threat to public health owing to the lack of effective prevention and therapeutics. D-Q7 is a D-type antimicrobial peptide (AMP) with potent sterilization activity against gram-negative ESKAPE pathogens; it is thus of considerable interest to evaluate whether D-Q7 represents a promising therapeutic candidate against this pathogen. Consequently, we found that D-Q7 was a potent antibacterial agent that killed colistin-resistant A. hydrophila 23-c-23 in vitro and in a mouse epicutaneous model of 23-c-23 infection. In addition, we found that gene3832, as a potential transmembrane autotransporter, is related to bacterial resistance to D-Q7. Importantly, our study here will help guide the future design and optimization of novel AMPs to combat colistin-resistant A. hydrophila.