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The primary treatment for infections typically involves antibiotics, which can lead to the emergence of multidrug-resistant strains. Therefore, there is a pressing need for safe and effective alternative methods. Phage therapy stands out as a promising approach. However, filamentous prophages (Pfs) commonly found in P. aeruginosa encode genes with phage defense activity, thereby reducing the efficacy of phage therapy. Through a genomic analysis of the Pf4 prophage, we identified a 102 bp gene co-transcribed with the upstream gene responsible for phage release (zot gene), giving rise to a 33-amino-acid polypeptide that we have named Pf4-encoded toxic polypeptide (PftP4). The overexpression of PftP4 demonstrated cellular toxicity in P. aeruginosa, with subcellular localization indicating its presence in the cell membrane and a subsequent increase in membrane permeability. Notably, PftP4 homologues are found in multiple Pf phages and exhibit specificity in their toxicity towards P. aeruginosa among the tested bacterial strains. Our study reveals that the novel Pf-encoded polypeptide PftP4 has the potential to selectively target and eradicate P. aeruginosa, offering valuable insights for combating P. aeruginosa infections.<\/jats:p>","DOI":"10.3390\/v17010112","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T09:01:02Z","timestamp":1736931662000},"page":"112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inovirus-Encoded Peptides Induce Specific Toxicity in Pseudomonas aeruginosa"],"prefix":"10.3390","volume":"17","author":[{"given":"Juehua","family":"Weng","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 511458, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-1746","authenticated-orcid":false,"given":"Yunxue","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 511458, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4840-7251","authenticated-orcid":false,"given":"Jiayu","family":"Gu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 511458, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 511458, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxue","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 511458, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"Key Laboratory of Tropical Oceanography, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 511458, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/35023079","article-title":"Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen","volume":"406","author":"Stover","year":"2000","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00248-013-0297-x","article-title":"Pseudomonas aeruginosa biofilms in disease","volume":"68","author":"Mulcahy","year":"2014","journal-title":"Microb. 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