AMPs are a group of gene-encoded small molecules distributed in all kingdoms with cationic, hydrophobic and amphipathic properties that contribute to their broad-spectrum of antimicrobial activity against invading microbes including bacteria, virus and fungi. But the discovery of antibiotic, regarded as a panacea in killing invading pathogens, made people forgetting the “natural antibiotic” that are AMPs. However, antibiotic resistance occurs very rapidly once the new antibiotic was applied in clinic, which surprisingly increases with alarming speed in recent years and has been considered as a serious health threats by the US government in 2013. This well recognized severity of antibiotic resistance and subsequent lack of new antibiotic development results in increased bacteria-induced mortality such as chronic lung infection by PA, the leading cause of mortality for CF patients. This has urged government (USA and Europe) and it’s also crucial to pursue new strategies in particular AMPs against bacteria infection (4). This project will at first investigate the host AMPs involved in PA infection and identify the pathogen associated molecule patterns (PAMPs) of PA that induce AMPs expression and the signaling pathway in this process. We will also map the profile of AMPs in human CF and non-CF lung and clarify up- and down-regulated AMPs by PA lung infection. The bactericidal effect of selected AMPs on PA infection will then be checked. Particularly sPLA2-IIA, one of AMPs with strong bactericidal activity through hydrolyzing bacterial membrane phospholipids (major components of bacterial membrane), will be investigated. Both selected AMP and sPLA2-IIA will be modified to get maximal bactericidal activity via different approaches as described in the main text. Once establishing the role of the target AMP in particular sPLA2-IIA variant in killing PA efficiently in vitro and in vivo, the AMP (sPLA2-IIA variant) will be optimized completely to reduce the toxicity but keep efficient bactericidal function. This will be performed by monitoring cytotoxicity and evaluating immunogenicity and bactericidal activity in cells and human leukocyte antigen (HLA)-humanized mice, respectively. If successful, the optimized AMP (sPLA2-IIA variant) can be considered as a potential new therapy against bacteria in particular during PA infection such as in CF but also in other infectious diseases.