More on new antibiotics! Superbugs have no chance! With AI & machine learning discovering new antibiotics will become something like child's play!
They used dogs for this study to test for safety! Apparently, these researchers were not dog owners.
"Decades of work has seemingly paid off with scientists developing a potent new synthetic molecule that swiftly knocked out 285 strains of gram-negative bacteria it was tested on, setting it up as a valuable ally in our fight against a looming superbug infection crisis. ..."
"... And it works fast. “LPC-233 can reduce bacterial viability by 100,000-fold within four hours,” ... Large scale synthesis of LPC-233 was first accomplished ..."
From the editor's summary and abstract:
"Editor’s summary
Lipid A biosynthesis is essential to the formation of the outer membrane of most Gram-negative bacteria and has been considered a potential target for antibiotic therapy. Zhao et al. have now characterized an inhibitor (LPC-233) of the UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC, which can specifically inhibit lipid A synthesis. Previous attempts to make LpxC-targeting antibiotics were limited by unfavorable cardiovascular toxicity. In contrast, preclinical evaluation of LPC-233 revealed promising in vitro and in vivo safety profiles, tight binding to LpxC with picomolar affinity, oral bioavailability, and bactericidal activity against a broad range of Gram-negative pathogens. These results support the further development of LpxC-targeting antibiotic therapies. ...
Abstract
The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non–hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications."
Synthetic Antibiotic Could Be Effective Against Drug-Resistant Superbugs Decades of work by a series of Duke investigators yields new drug, patents and a startup company
Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens (no public access)
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