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U.S.A."],"published-print":{"date-parts":[[2024,4,9]]},"abstract":"<jats:p>\n                    Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    . We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens\n                    <jats:italic>E. coli<\/jats:italic>\n                    and\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    . Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-\u03b2-lactamase, metallo-\u03b2-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2317274121","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T13:59:45Z","timestamp":1712325585000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":26,"title":["Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9974-578X","authenticated-orcid":false,"given":"Douglas L.","family":"Huseby","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, BMC, Uppsala University","place":["Uppsala, 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