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Most of the cationic NCR peptides have antimicrobial activity and the potential to tackle antimicrobial resistance with their novel modes of action. This work focuses on the antibacterial activity of the NCR169 peptide derivatives as we previously demonstrated that the C-terminal sequence of NCR169 (NCR169C17\u201338) has antifungal activity, affecting the viability, morphology, and biofilm formation of various Candida species. Here, we show that NCR169C17\u201338 and its various substituted derivatives are also able to kill ESKAPE pathogens such as Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. The replacement of the two cysteines with serines enhanced the antimicrobial activity against most of the tested bacteria, indicating that the formation of a disulfide bridge is not required. As tryptophan can play role in the interaction with bacterial membranes and thus in antibacterial activity, we replaced the tryptophans in the NCR169C17\u201338C12,17\/S sequence with various modified tryptophans, namely 5-methyl tryptophan, 5-fluoro tryptophan, 6-fluoro tryptophan, 7-aza tryptophan, and 5-methoxy tryptophan, in the synthesis of NCR169C17\u201338C12,17\/S analogs. The results demonstrate that the presence of modified fluorotryptophans can significantly enhance the antimicrobial activity without notable hemolytic effect, and this finding could be beneficial for the further development of new AMPs from the members of the NCR peptide family.<\/jats:p>","DOI":"10.3390\/ijms24032694","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T02:29:03Z","timestamp":1675218543000},"page":"2694","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Enhanced Antibacterial Activity of Substituted Derivatives of NCR169C Peptide"],"prefix":"10.3390","volume":"24","author":[{"given":"Dian H. O.","family":"Howan","sequence":"first","affiliation":[{"name":"Department of Medical Chemistry, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e1ndor","family":"Jenei","sequence":"additional","affiliation":[{"name":"Biological Research Centre, Institute of Plant Biology, H-6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e1nos","family":"Szolomajer","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9493-7395","authenticated-orcid":false,"given":"Gabriella","family":"Endre","sequence":"additional","affiliation":[{"name":"Biological Research Centre, Institute of Plant Biology, H-6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c9va","family":"Kondorosi","sequence":"additional","affiliation":[{"name":"Biological Research Centre, Institute of Plant Biology, H-6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e1bor K.","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, H-6720 Szeged, Hungary"},{"name":"MTA-SZTE Biomimetic Systems Research Group, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110","DOI":"10.4103\/2045-080X.186181","article-title":"Book Review: Tackling Drug-Resistant Infections Globally","volume":"7","author":"Shankar","year":"2016","journal-title":"Arch. 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