Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria

• 成果类型: Article
• 署名作者: Huseby, Douglas L.; Cao, Sha; Zamaratski, Edouard; Sooriyaarachchi, Sanjeewani; Ahmad, Shabbir; Bergfors, Terese; Krasnova, Laura; Pelss, Juris; Ikaunieks, Martins; Loza, Einars; Katkevics, Martins; Bobileva, Olga; Cirule, Helena; Gukalova, Baiba; Grinberga, Solveiga; Backlund, Maria; Simoff, Ivailo; Leber, Anna T.; Berruga-Fernandez, Talia; Antonov, Dmitry; Konda, Vivekananda R.; Lindstrom, Stefan; Olanders, Gustav; Brandt, Peter; Baranczewski, Pawel; Lundberg, Carina Vingsbo; Liepinsh, Edgars; Suna, Edgars; Jones, T. Alwyn; Mowbray, Sherry L.; Hughes, Diarmaid; Karlen, Anders
• 署名单位: Uppsala University; Uppsala University; Uppsala University; Latvian Institute of Organic Synthesis; Uppsala University; Uppsala University; SciLifeLab; Statens Serum Institut
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9329
• DOI: 10.1073/pnas.2317274121
• 发表日期: 2024-04-09
• 关键词: discovery

摘要

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-beta-lactamase, metallo-beta-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.