Author: Krasnova, Laura ; Loza, Einars ; Bergfors, Terese ; Konda, Vivekananda R. ; Huseby, Douglas L. ; Olanders, Gustav ; Vingsbo Lundberg, Carina ; Sooriyaarachchi, Sanjeewani ; Cao, Sha ; Jones, T. Alwyn ; Backlund, Maria ; Simoff, Ivailo ; Leber, Anna T. ; Bobileva, Olga ; Lindström, Stefan ; Gukalova, Baiba ; Cirule, Helena ; Mowbray, Sherry L. ; Ahmad, Shabbir ; Hughes, Diarmaid ; Pelss, Juris ; Zamaratski, Edouard ; Katkevics, Martins ; Antonov, Dmitry ; Ikaunieks, Martins ; Karlén, Anders ; Grinberga, Solveiga ; Brandt, Peter ; Liepinsh, Edgars ; Suna, Edgars ; Berruga-Fernández, Talía ; Baranczewski, Pawel

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Negative Bacterial Infections	Preclinical	Sweden	University of Uppsala	05 Apr 2024

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