8QKA

Structure of K. pneumoniae LpxH in complex with JEDI-852

Summary for 8QKA

• Entry DOI: 10.2210/pdb8qka/pdb
• Descriptor: UDP-2,3-diacylglucosamine hydrolase, MANGANESE (II) ION, 2-[methyl(methylsulfonyl)amino]-~{N}-(4-piperidin-1-ylsulfonylphenyl)benzamide, ... (4 entities in total)
• Functional Keywords: lipid a biosynthesis pathway endotoxin udp-diacyl-glucosamine lipid x gram-negative bacteria lipopolysaccharides, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 28570.38

Authors

Sooriyaarachchi, S.,Bergfors, T.,Jones, T.A.,Mowbray, S.L. (deposition date: 2023-09-14, release date: 2024-04-17)

Primary citation

Huseby, D.L.,Cao, S.,Zamaratski, E.,Sooriyaarachchi, S.,Ahmad, S.,Bergfors, T.,Krasnova, L.,Pelss, J.,Ikaunieks, M.,Loza, E.,Katkevics, M.,Bobileva, O.,Cirule, H.,Gukalova, B.,Grinberga, S.,Backlund, M.,Simoff, I.,Leber, A.T.,Berruga-Fernandez, T.,Antonov, D.,Konda, V.R.,Lindstrom, S.,Olanders, G.,Brandt, P.,Baranczewski, P.,Vingsbo Lundberg, C.,Liepinsh, E.,Suna, E.,Jones, T.A.,Mowbray, S.L.,Hughes, D.,Karlen, A.
Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.
Proc.Natl.Acad.Sci.USA, 121:e2317274121-e2317274121, 2024

PubMed 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 . 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 and . 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.

PubMed: 38579010
DOI: 10.1073/pnas.2317274121

Experimental method

X-RAY DIFFRACTION (2 Å)