Design and evaluation of pyridinyl sulfonyl piperazine LpxH Inhibitors with potent antibiotic activity against enterobacterales

DOI: 10.1021/jacsau.4c00731

Authors: Amanda F. Ennis (Duke University) , C. Skyler Cochrane (Duke University) , Patrick A. Dome (Duke University) , Pyeonghwa Jeong (Duke University) , Jincheng Yu (Duke University) , Hyejin Lee (Duke University) , Carly S. Williams (Duke University) , Yang Ha (Lawrence Berkeley National Laboratory) , Weitao Yang (Duke University) , Pei Zhou (Duke University) , Jiyong Hong (Duke University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Jacs Au

State: Published (Approved)
Published: November 2024
Diamond Proposal Number(s): 442

Abstract: Enterobacterales, a large order of Gram-negative bacteria, including Escherichia coli and Klebsiella pneumoniae, are major causes of urinary tract and gastrointestinal infections, pneumonia, and other diseases in healthcare settings and communities. ESBL-producing Enterobacterales and carbapenem-resistant Enterobacterales can break down commonly used antibiotics, with some strains being resistant to all available antibiotics. This public health threat necessitates the development of novel antibiotics, ideally targeting new pathways in these bacteria. Gram-negative bacteria possess an outer membrane enriched with lipid A, a saccharolipid that serves as the membrane anchor of lipopolysaccharides and the active component of the bacterial endotoxin, causing septic shock. The biosynthesis of lipid A is crucial for the viability of Gram-negative bacteria, and as an essential enzyme in this process, LpxH has emerged as a promising target for developing novel antibiotics against multidrug-resistant Gram-negative pathogens. Here, we report the development of pyridinyl sulfonyl piperazine LpxH inhibitors. Among them, ortho-substituted pyridinyl compounds significantly boost LpxH inhibition and antibiotic activity over the original phenyl series. Structural and QM/MM analyses reveal that these improved activities are primarily due to the enhanced interaction between F141 of the LpxH insertion lid and the pyridinyl group. Incorporation of the N-methyl-N-phenyl-methanesulfonamide moiety into the pyridinyl sulfonyl piperazine backbone results in JH-LPH-106 and JH-LPH-107, both of which exhibit potent antibiotic activity against wild-type Enterobacterales such as K. pneumoniae and E. coli. JH-LPH-107 exhibits a low rate of spontaneous resistance and a high safety window in vitro, rendering it an excellent lead for further clinical development.

Journal Keywords: antibiotics; Gram-negative bacteria; Enterobacterales; lipid A; LpxH; pyridinyl sulfonyl piperazine; N-methyl-N-phenyl-methanesulfonamide

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: 5.0.2, 5.0.3 at ALS

Added On: 13/11/2024 10:51

Documents:
ennis-et-al-2024-design-and-evaluation-of-pyridinyl-sulfonyl-piperazine-lpxh-inhibitors-with-potent-antibiotic-activity.pdf

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)