{"entity": "researcher", "timestamp": "2026-06-17T19:09:29.719Z", "family": "Karl\u00e9n", "given": "Anders", "initials": "A", "orcid": "0000-0001-9512-6981", "affiliations": ["Department of Medicinal Chemistry, BMC, Uppsala University, Uppsala SE-75123, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/980cd0dc5fa140909f6cadbef7a0b8c4.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/980cd0dc5fa140909f6cadbef7a0b8c4"}}, "publications": [{"entity": "publication", "iuid": "b286a07ac16642dd8c711e02c12dc05d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b286a07ac16642dd8c711e02c12dc05d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b286a07ac16642dd8c711e02c12dc05d"}}, "title": "Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.", "authors": [{"family": "Huseby", "given": "Douglas L", "initials": "DL", "orcid": "0000-0001-9974-578X", "researcher": {"href": "https://publications.scilifelab.se/researcher/7c5675b30e74444f8448221f038e3b7b.json"}}, {"family": "Cao", "given": "Sha", "initials": "S"}, {"family": "Zamaratski", "given": "Edouard", "initials": "E", "orcid": "0009-0003-2707-3648", "researcher": {"href": "https://publications.scilifelab.se/researcher/dbf26315a27f45298d524da933eae7e7.json"}}, {"family": "Sooriyaarachchi", "given": "Sanjeewani", "initials": "S"}, {"family": "Ahmad", "given": "Shabbir", "initials": "S", "orcid": "0000-0003-2374-1197", "researcher": {"href": "https://publications.scilifelab.se/researcher/d55c86a429184f4db3e705eca9a96271.json"}}, {"family": "Bergfors", "given": "Terese", "initials": "T", "orcid": "0000-0002-6463-9116", "researcher": {"href": "https://publications.scilifelab.se/researcher/dda8871f860d483ebb92b7244b211ef0.json"}}, {"family": "Krasnova", "given": "Laura", "initials": "L"}, {"family": "Pelss", "given": "Juris", "initials": "J"}, {"family": "Ikaunieks", "given": "Martins", "initials": "M"}, {"family": "Loza", "given": "Einars", "initials": "E"}, {"family": "Katkevics", "given": "Martins", "initials": "M", "orcid": "0000-0003-1547-0075", "researcher": {"href": "https://publications.scilifelab.se/researcher/4619d8e8a1f344c19d6fabfe34aa0482.json"}}, {"family": "Bobileva", "given": "Olga", "initials": "O", "orcid": "0000-0001-9600-1603", "researcher": {"href": "https://publications.scilifelab.se/researcher/0a65f3e28d1e4185a962f4fda120b039.json"}}, {"family": "Cirule", "given": "Helena", "initials": "H"}, {"family": "Gukalova", "given": "Baiba", "initials": "B", "orcid": "0000-0002-7057-4726", "researcher": {"href": "https://publications.scilifelab.se/researcher/575ede058f6945b1b524308f4e671d9a.json"}}, {"family": "Grinberga", "given": "Solveiga", "initials": "S"}, {"family": "Backlund", "given": "Maria", "initials": "M", "orcid": "0000-0002-6253-816X", "researcher": {"href": "https://publications.scilifelab.se/researcher/bffc6d0b93b64dafa4c17abf7910964e.json"}}, {"family": "Simoff", "given": "Ivailo", "initials": "I"}, {"family": "Leber", "given": "Anna T", "initials": "AT"}, {"family": "Berruga-Fern\u00e1ndez", "given": "Tal\u00eda", "initials": "T"}, {"family": "Antonov", "given": "Dmitry", "initials": "D"}, {"family": "Konda", "given": "Vivekananda R", "initials": "VR"}, {"family": "Lindstr\u00f6m", "given": "Stefan", "initials": "S", "orcid": "0009-0009-7396-9529", "researcher": {"href": "https://publications.scilifelab.se/researcher/fed14c3020094d9a8ca1ace96cbbe7b2.json"}}, {"family": "Olanders", "given": "Gustav", "initials": "G", "orcid": "0000-0003-4713-8368", "researcher": {"href": "https://publications.scilifelab.se/researcher/835ad31069ca4f7897946baacc3a25a1.json"}}, {"family": "Brandt", "given": "Peter", "initials": "P"}, {"family": "Baranczewski", "given": "Pawel", "initials": "P", "orcid": "0000-0001-5772-6791", "researcher": {"href": "https://publications.scilifelab.se/researcher/47f7af2466c14275a42aad4a431b2dcb.json"}}, {"family": "Vingsbo Lundberg", "given": "Carina", "initials": "C", "orcid": "0000-0003-3408-3353", "researcher": {"href": "https://publications.scilifelab.se/researcher/068b2ddd87fd4cc9bd66e9f4d6030ff1.json"}}, {"family": "Liepinsh", "given": "Edgars", "initials": "E", "orcid": "0000-0003-2213-8337", "researcher": {"href": "https://publications.scilifelab.se/researcher/ba6ab471eec7447b955e63f391162b9b.json"}}, {"family": "Suna", "given": "Edgars", "initials": "E"}, {"family": "Jones", "given": "T Alwyn", "initials": "TA"}, {"family": "Mowbray", "given": "Sherry L", "initials": "SL", "orcid": "0000-0002-0732-6367", "researcher": {"href": "https://publications.scilifelab.se/researcher/03e5c02bfd3a4a2e8c413944ea30158f.json"}}, {"family": "Hughes", "given": "Diarmaid", "initials": "D", "orcid": "0000-0002-7456-9182", "researcher": {"href": "https://publications.scilifelab.se/researcher/19a78e8c5738475ab04ce3922a10e7e1.json"}}, {"family": "Karl\u00e9n", "given": "Anders", "initials": "A", "orcid": "0000-0001-9512-6981", "researcher": {"href": "https://publications.scilifelab.se/researcher/980cd0dc5fa140909f6cadbef7a0b8c4.json"}}], "type": "journal article", "published": "2024-04-09", "journal": {"title": "Proc. Natl. Acad. Sci. U.S.A.", "issn": "1091-6490", "volume": "121", "issue": "15", "pages": "e2317274121", "issn-l": "0027-8424"}, "abstract": "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 Escherichia coli. 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 E. coli and Klebsiella pneumoniae. 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.", "doi": "10.1073/pnas.2317274121", "pmid": "38579010", "labels": {"Drug Discovery and Development": "Collaborative"}, "xrefs": [], "notes": [], "created": "2024-04-06T07:12:33.278Z", "modified": "2025-10-17T13:05:07.381Z"}]}