Researchers at Duke University have developed a synthetic molecule, LPC-233, which is effective by inhibiting lipid synthesis in the outer membrane of Gram-negative bacteria such as E. coli and Salmonella. It has demonstrated remarkable efficacy in animal studies, demonstrated potential to combat resistant urinary tract infections, and demonstrated low resistance mutation rates.
Decades of research by a series of researchers have led to breakthrough drugs, groundbreaking patents, and the launch of new start-ups.
Decades of Scientific Journey at Duke University Discover New Antibiotic Approaches to Combat Gram-Negative Bacteria such as Salmonella, Pseudomonas, and E. coli, Common Causes of Urinary Tract Infections (UTIs) it was done. This synthetic molecule is fast acting and durable in animal studies.
It works by interfering with the bacteria’s ability to build its outer lipid layer, the skin, so to speak.
“If you block the synthesis of the bacterial outer membrane, the bacteria can’t survive without it,” said lead investigator Pei Zhou, professor of chemistry at Duke School of Medicine. “Our compound is very good and very powerful.”
This compound, called LPC-233, is a small molecule that has proven effective in disrupting outer membrane lipid biosynthesis in all Gram-negative bacteria tested. Co-authors at the University of Lille, France, tested the virus against a collection of 285 bacterial strains, including strains highly resistant to commercial antibiotics, and killed all of them.
And it works fast. “LPC-233 can reduce bacterial viability by a factor of 100,000 within four hours,” Zhou said.
The compound is also persistent enough to survive into the urinary tract after oral administration, making it a potentially important tool against persistent urinary tract infections (UTIs).
According to the paper describing the results, tests performed at high concentrations of the compound showed “a very low incidence of spontaneous resistance mutations in these bacteria.” scientific translational medicine.
In animal studies, this compound has been successfully administered orally and intravenously or injected into the abdomen. In one experiment, the new compound rescued mice from what would have been a lethal dose of multidrug-resistant bacteria.
The search for this compound took decades due to the required specificity and safety of this synthetic molecule.
Zhou credits his late colleague, former Duke Biochemistry Commissioner Christian Raetz, who began the work decades ago. “He spent his entire career on this path,” Zhou said. “Dr. Letts proposed a conceptual blueprint for this pathway in his 1980s, but it took him more than two decades to identify all the parties,” said Zhou. .
The new drug targets an enzyme called LpxC, the second enzyme in the ‘Reetz pathway’, which is essential for the production of outer membrane lipids in Gram-negative bacteria.
Raetz joined Duke in 1993 as chairman of the biochemistry division after research into this pathway at Merck failed to produce a successful clinical candidate. Merck’s antibiotics worked, but they were only effective against E. coli, so they weren’t commercially viable and the drug companies discontinued them.
Zhou, who came to Duke University in 2001, said, “He actually recruited me to Duke University to work on this enzyme, initially from a structural biology perspective.” .
Zhou and Raetz have elucidated the structure of the LpxC enzyme and revealed molecular details of several potential inhibitors. “We realized that if we tweak the compound, we could improve it,” Zhou said. Since then, Zhou has been working with his colleague Duke Chemistry Professor Eric Thun to develop more potent LpxC inhibitors.
The first human trials of LpxC inhibitors failed due to cardiovascular toxicity. The focus of the Duke group’s subsequent research was to avoid cardiovascular effects while maintaining the compound’s potency.
They have worked on over 200 different versions of enzyme inhibitors, constantly seeking greater safety and greater potency. Compound #233 was the winner, although other compounds were more or less successful.
LPC-233 fits into the binding spot of the LpxC enzyme and interferes with the action of the LpxC enzyme. “This is a great way to inhibit lipid production,” Zhou said. “System has failed.”
According to Zhou, the compound is made more durable by an amazing two-step process. After initial binding to LpxC, the enzyme-inhibitor complex changes its shape somewhat and becomes a more stable complex.
The lifetime of inhibitors that bind to this more stable complex is longer than that of bacteria. “Enzymes have a semi-permanent effect, so I think that contributes to potency,” he says. “Even after the unbound drug is metabolized in the body, the enzyme is still inhibited because the dissociation process of the inhibitor is so slow,” Zhou said.
Multiple patents have been filed for this series of compounds, and Toone and Zhou co-founded a company called Valanbio Therapeutics, Inc. to conduct a phase 1 study to evaluate the safety and efficacy of LPC-233. We are looking for partners to conduct clinical trials. human.
“All these studies were done in animals,” Zhou said. “Eventually, cardiovascular safety needs to be tested in humans.”
Reference: “Preclinical Safety and Efficacy Characterization of LpxC Inhibitors Against Gram-Negative Pathogens” Jinshi Zhao, C. Skyler Cochrane, Javaria Najeeb, David Gooden, Carly Sciandra, Ping Fan, Nadine Lemaitre, Kate Newns, Robert A. Nicholas, Ziqiang Guan, Joshua T. Thaden, Vance G. Fowler, Ivan Spasojevic, Florent Sebbane, Eric J. Toone, Clayton Duncan, Richard Gammons, Pei Zhou, August 9, 2023, scientific translational medicine.
DOI: 10.1126/scitranslmed.adf5668
Large-scale synthesis of LPC-233 was first achieved by David Gooden at the Duke Small Molecule Synthesis Facility. Vance Fowler and Joshua Thaden (Duke School of Medicine), Ziqiang Guan (Biochemistry), and Ivan Spasojevic (Duke PK/PD Core) assisted with in vivo studies, mass spectrometry, and pharmacokinetic analyses.
This research was supported by the following grants: National Institutes of Health (R01 GM115355, AI094475, AI152896, AI148366), North Carolina Center for Biotechnology (2016-TEG-1501), and National Cancer Institute Comprehensive Cancer Center Core Grant (P30CA014236).
