Gram-negative bacteria: Synthetic antibiotic strategy
17 August 2023
Scientists at Duke University report they have developed a synthetic antibiotic that could be effective against drug-resistant superbugs and bacteria such as Salmonella, Pseudomonas, and E. coli.
Their findings are published in Science Translational Medicine in an article titled, “Preclinical Safety and Efficacy Characterization of an LpxC Inhibitor Against Gram-Negative Pathogens.”
“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 researchers wrote. “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.”
“If you disrupt the synthesis of the bacterial outer membrane, the bacteria cannot survive without it,” said lead investigator Pei Zhou, PhD, a professor of biochemistry at the Duke School of Medicine. “Our compound is very good and very potent.”
In animal studies, their compound LPC-233 was administered orally and intravenously or injected into the abdomen. The researchers observed the compound rescued mice with a fatal dose of multi-drug-resistant bacteria.
Zhou credits his late colleague, former Duke biochemistry chair Christian Raetz, MD, PhD, for starting the search decades ago. “He spent his entire career working on this pathway,” Zhou said. “Dr. Raetz proposed a conceptual blueprint for this pathway in the 1980s, and it took him over two decades to identify all of the players,” Zhou said.
The new drug’s target is an enzyme called LpxC which is the second enzyme in the “Raetz pathway” and is essential to making the outer membrane lipid in gram-negative bacteria.
Zhou and Raetz had solved the structure of the LpxC enzyme and revealed molecular details of a few potential inhibitors. “We realized that we could tweak the compound to make it better,” Zhou said. Since then, Zhou has been working with his colleague, Duke chemistry professor Eric Toone, PhD, to make more potent LpxC inhibitors.
The first human trial of LpxC inhibitors failed because of cardiovascular toxicity. They worked on more than 200 different versions of the enzyme inhibitor, always searching for better safety and more potency. Other compounds worked to varying degrees, but compound number 233 succeeded.
“All of these studies were done in animals,” Zhou said. “Ultimately the cardiovascular safety needs to be tested in humans.” Their findings provide hope for a potential strategy to defeat drug-resistant superbugs.
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Also published on: Genengnews.com
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