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Novel compounds and\/or therapeutic strategies are required to face the challenge posed, in particular, by Gram-negative bacteria. Here we assess the combined effect of potent cell-wall synthesis inhibitors with either natural or synthetic peptides that can act on the outer-membrane. Thus, several linear peptides, either alone or combined with vancomycin or nisin, were tested against selected Gram-negative pathogens, and the best one was improved by further engineering. Finally, peptide D-11 and vancomycin displayed a potent antimicrobial activity at low \u03bcM concentrations against a panel of relevant Gram-negative pathogens. This combination was highly active in biological fluids like blood, but was non-hemolytic and non-toxic against cell lines. We conclude that vancomycin and D-11 are safe at &gt;50-fold their MICs. Based on the results obtained, and as a proof of concept for the newly observed synergy, a <jats:italic>Pseudomonas aeruginosa<\/jats:italic> mouse infection model experiment was also performed, showing a 4 log<jats:sub>10<\/jats:sub> reduction of the pathogen after treatment with the combination. This approach offers a potent alternative strategy to fight (drug-resistant) Gram-negative pathogens in humans and mammals.<\/jats:p>","DOI":"10.1038\/s42003-020-01511-1","type":"journal-article","created":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T11:02:41Z","timestamp":1609758161000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Outer-membrane-acting peptides and lipid II-targeting antibiotics cooperatively kill Gram-negative pathogens"],"prefix":"10.1038","volume":"4","author":[{"given":"Qian","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Cebri\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Montalb\u00e1n-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5596-7735","authenticated-orcid":false,"given":"Oscar P.","family":"Kuipers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,4]]},"reference":[{"key":"1511_CR1","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/cbdd.12478","volume":"85","author":"EE Gill","year":"2015","unstructured":"Gill, E. 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