Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria
Douglas L. Huseby, Sha Cao, Edouard Zamaratski, Sanjeewani Sooriyaarachchi, Shabbir Ahmad, Terese Bergfors, L. Krasnova, Juris Pelšs, Martins Ikaunieks, Einārs Loža, Mārtiņš Katkevičs, Olga Bobiļeva, Helena Cirule, Baiba Gukalova, Solveiga Grı̄nberga, Maria Backlund, Ivailo Simoff, Anna Tamara Leber, Talía Berruga-Fernández, Dmitry M. Antonov, Vivekananda R. Konda, Stefan Lindström, Gustav Olanders, Peter Brandt, Paweł Baranczewski, Carina Vingsbo Lundberg, Edgars Liepinsh, Edgars Sūna, T. Alwyn Jones, Sherry L. Mowbray, Diarmaid Hughes, Anders Karlén
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-β-lactamase, metallo-β-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.