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Microcin J25, a potent and highly stable antimicrobial peptide active against Enterobacteriaceae, is a candidate antimicrobial against multiple <jats:italic>Salmonella<\/jats:italic> species. Emerging evidence supports the hypothesis that the composition of the microbiota of the gastrointestinal tract prevents a variety of diseases by preventing infectious agents from proliferating. Reducing clearance of off\u2010target bacteria may decrease susceptibility to secondary infection. Of the Enterobacteriaceae susceptible to microcin J25, <jats:italic>Escherichia coli<\/jats:italic> are the most abundant within the human gut. To explore the modulation of specificity, a collection of 207 mutants encompassing 12 positions in both the ring and loop of microcin J25 was built and tested for activity against <jats:italic>Salmonella<\/jats:italic> and <jats:italic>E. coli<\/jats:italic> strains. As has been found previously, mutational tolerance of ring residues was lower than loop residues, with 22% and 51% of mutations, respectively, retaining activity toward at least one target within the target organism test panel. The multitarget screening elucidated increased mutational tolerance at position G2, G3, and G14 than previously identified in panels composed of single targets. Multiple mutations conferred differential response between the different targets. Examination of specificity differences between mutants found that 30% showed significant improvements to specificity toward any of the targets. Generation and testing of a combinatorial library designed from the point\u2010mutant study revealed that microcin J25<jats:sup>I13T<\/jats:sup> reduces off\u2010target activity toward commensal human\u2010derived <jats:italic>E. coli<\/jats:italic> isolates by 81% relative to <jats:italic>Salmonella enterica<\/jats:italic> serovar Enteritidis. These in vitro specificity improvements are likely to improve in vivo treatment efficacy by reducing clearance of commensal bacteria in the gastrointestinal tract of hosts.<\/jats:p>","DOI":"10.1002\/bit.26772","type":"journal-article","created":{"date-parts":[[2018,6,25]],"date-time":"2018-06-25T13:12:51Z","timestamp":1529932371000},"page":"2394-2404","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Multispecies activity screening of microcin J25 mutants yields antimicrobials with increased specificity toward pathogenic <i>Salmonella<\/i> species relative to human commensal <i>Escherichia coli<\/i>"],"prefix":"10.1002","volume":"115","author":[{"given":"Seth C.","family":"Ritter","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota\u2014Twin Cities  Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike L.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota\u2014Twin Cities  Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiannis N.","family":"Kaznessis","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota\u2014Twin Cities  Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3561-9463","authenticated-orcid":false,"given":"Benjamin J.","family":"Hackel","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota\u2014Twin Cities  Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,7,20]]},"reference":[{"key":"e_1_2_7_1_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.05.017"},{"key":"e_1_2_7_1_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10989-010-9235-7"},{"key":"e_1_2_7_1_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-012-4041-0"},{"key":"e_1_2_7_1_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/sb500090b"},{"key":"e_1_2_7_1_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201100702"},{"key":"e_1_2_7_1_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/b516237h"},{"key":"e_1_2_7_1_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1139"},{"key":"e_1_2_7_1_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/1751-7915.12041"},{"key":"e_1_2_7_1_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep40695"},{"key":"e_1_2_7_1_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00227-15"},{"key":"e_1_2_7_1_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph9040060"},{"key":"e_1_2_7_1_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756283X13482996"},{"key":"e_1_2_7_1_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02488-10"},{"key":"e_1_2_7_1_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079563"},{"key":"e_1_2_7_1_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.5b00156"},{"key":"e_1_2_7_1_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15028"},{"key":"e_1_2_7_1_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.41.12.5798-5802.2003"},{"key":"e_1_2_7_1_19_1","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-148-7-2019"},{"key":"e_1_2_7_1_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201102190"},{"key":"e_1_2_7_1_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.7b00417"},{"key":"e_1_2_7_1_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3975"},{"key":"e_1_2_7_1_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-1010-6"},{"key":"e_1_2_7_1_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)74008-3"},{"key":"e_1_2_7_1_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm009"},{"key":"e_1_2_7_1_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2np20070h"},{"key":"e_1_2_7_1_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2017.30"},{"key":"e_1_2_7_1_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1499"},{"key":"e_1_2_7_1_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.25710"},{"key":"e_1_2_7_1_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0058530"},{"key":"e_1_2_7_1_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.06.010"},{"key":"e_1_2_7_1_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.1.292"},{"key":"e_1_2_7_1_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/35012500"},{"key":"e_1_2_7_1_34_1","unstructured":"O\u2019Neill J. 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