Decades of work by a series of researchers has led to a groundbreaking drug, innovative patents, and the launch of a new startup.
A scientific journey decades in the making at Duke University has discovered a novel antibiotic approach to combat gram-negative bacteria, including Salmonella, Pseudomonas, and E. coli, which are often responsible for urinary tract infections (UTIs). The synthetic molecule works fast and is durable in animal tests.
“If you disrupt the synthesis of the bacterial outer membrane, the bacteria cannot survive without it,” said lead investigator Pei Zhou, a professor of biochemistry at the Duke School of Medicine. “Our compound is very good and very potent.”
And it works fast. “LPC-233 can reduce bacterial viability by 100,000-fold within four hours,” Zhou said.
The compound is also tenacious enough to survive all the way to the urinary tract after oral administration, which may make it a vital tool against stubborn urinary tract infections (UTIs).
In animal studies, the compound was successful when administered orally and intravenously or injected into the abdomen. In one experiment, mice given what should have been a fatal dose of multidrug-resistant bacteria were rescued by the new compound.
The search for this compound took decades because of the specificity and safety required of the synthetic molecule.
Zhou credits his late colleague, former Duke Biochemistry Chair Christian Raetz, 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.
Raetz joined Duke as the chairman of biochemistry in 1993 after his work on this pathway at Merck & Co. had failed to produce a successful clinical candidate. The Merck antibiotic worked, but only against E. coli, so it wasn’t commercially viable and the pharmaceutical company dropped it.
“He actually recruited me to Duke to work on this enzyme, initially just from the structural biology perspective,” said Zhou, who came to Duke in 2001.
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, to make more potent LpxC inhibitors.
The first human trial of LpxC inhibitors had failed because of cardiovascular toxicity. The focus of the Duke group’s subsequent work was to avoid cardiovascular effects while maintaining the potency of the compound.
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 was the winner.
LPC-233 fits a binding spot on the LpxC enzyme and prevents it from doing its work. “It fits in the right way to inhibit formation of the lipid,” Zhou said. “We’re jamming the system.”
Adding to its durability, the compound works by a remarkable two-step process, Zhou said. After the initial binding to LpxC, the enzyme-inhibitor complex changes its shape somewhat to become an even more stable complex.
The lifetime of the inhibitor binding in this more stable complex is longer than the lifetime of the bacteria. “We think that contributes to the potency, as it has a semi-permanent effect on the enzyme,” he said. “Even after the unbound drug is metabolized by the body, the enzyme is still inhibited due to the extremely slow inhibitor dissociation process,” Zhou said.
There are multiple patents being filed on the series of compounds, and Toone and Zhou have co-founded a company called Valanbio Therapeutics, Inc. which will be looking for partners to bring LPC-233 through phase 1 clinical trials to assess safety and efficacy in humans.
“All of these studies were done in animals,” Zhou said. “Ultimately the cardiovascular safety needs to be tested in humans.”
Reference: “Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens” by 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 Gammans and Pei Zhou, 9 August 2023, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adf5668
Large scale synthesis of LPC-233 was first accomplished 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) helped with in vivo studies, mass spectrometry, and pharmacokinetics analysis.
This work was supported by grants from National Institutes of Health (R01 GM115355, AI094475, AI152896, AI148366), the North Carolina Biotechnology Center (2016-TEG-1501), and a National Cancer Institute Comprehensive Cancer Center Core Grant (P30CA014236).
![](https://www.nanoappsmedical.com/wp-content/uploads/2017/05/spacer.jpg)
News
The Silent Battle Within: How Your Organs Choose Between Mom and Dad’s Genes
Research reveals that selective expression of maternal or paternal X chromosomes varies by organ, driven by cellular competition. A new study published today (July 26) in Nature Genetics by the Lymphoid Development Group at the MRC [...]
Study identifies genes increasing risk of severe COVID-19
Whether or not a person becomes seriously ill with COVID-19 depends, among other things, on genetic factors. With this in mind, researchers from the University Hospital Bonn (UKB) and the University of Bonn, in [...]
Small regions of the brain can take micro-naps while the rest of the brain is awake and vice versa
Sleep and wake: They're totally distinct states of being that define the boundaries of our daily lives. For years, scientists have measured the difference between these instinctual brain processes by observing brain waves, with [...]
Redefining Consciousness: Small Regions of the Brain Can Take Micro-Naps While the Rest of the Brain Is Awake
The study broadly reveals how fast brain waves, previously overlooked, establish fundamental patterns of sleep and wakefulness. Scientists have developed a new method to analyze sleep and wake states by detecting ultra-fast neuronal activity [...]
AI Reveals Health Secrets Through Facial Temperature Mapping
Researchers have found that different facial temperatures correlate with chronic illnesses like diabetes and high blood pressure, and these can be detected using AI with thermal cameras. They highlight the potential of this technology [...]
Breakthrough in aging research: Blocking IL-11 extends lifespan and improves health in mice
In a recent study published in the journal Nature, a team of researchers used murine models and various pharmacological and genetic approaches to examine whether pro-inflammatory signaling involving interleukin (IL)-11, which activates signaling molecules such [...]
Promise for a universal influenza vaccine: Scientists validate theory using 1918 flu virus
New research led by Oregon Health & Science University reveals a promising approach to developing a universal influenza vaccine—a so-called "one and done" vaccine that confers lifetime immunity against an evolving virus. The study, [...]
New Projects Aim To Pioneer the Future of Neuroscience
One study will investigate the alterations in brain activity at the cellular level caused by psilocybin, the psychoactive substance found in “magic mushrooms.” How do neurons respond to the effects of magic mushrooms? What [...]
Decoding the Decline: Scientific Insights Into Long COVID’s Retreat
Research indicates a significant reduction in long COVID risk, largely due to vaccination and the virus’s evolution. The study analyzes data from over 441,000 veterans, showing lower rates of long COVID among vaccinated individuals compared [...]
Silicon Transformed: A Breakthrough in Laser Nanofabrication
A new method enables precise nanofabrication inside silicon using spatial light modulation and laser pulses, creating advanced nanostructures for potential use in electronics and photonics. Silicon, the cornerstone of modern electronics, photovoltaics, and photonics, [...]
Caught in the actinium: New research could help design better cancer treatments
The element actinium was first discovered at the turn of the 20th century, but even now, nearly 125 years later, researchers still don't have a good grasp on the metal's chemistry. That's because actinium [...]
Innovative Light-Controlled Drugs Could Revolutionize Neuropathic Pain Treatment
A team of researchers from the Institute for Bioengineering of Catalonia (IBEC) has developed light-activated derivatives of the anti-epileptic drug carbamazepine to treat neuropathic pain. Light can be harnessed to target drugs to specific [...]
Green Gold: Turning E-Waste Into a Treasure Trove of Rare Earth Metals
Scientists are developing a process inspired by nature that efficiently recovers europium from old fluorescent lamps. The approach could lead to the long-awaited recycling of rare earth metals. A small molecule that naturally serves [...]
Cambridge Study: AI Chatbots Have an “Empathy Gap,” and It Could Be Dangerous
A new study suggests a framework for “Child Safe AI” in response to recent incidents showing that many children perceive chatbots as quasi-human and reliable. A study has indicated that AI chatbots often exhibit [...]
Nanoparticle-based delivery system could offer treatment for diabetics with rare insulin allergy
Up to 3% of people with diabetes have an allergic reaction to insulin. A team at Forschungszentrum Jülich has now studied a method that could be used to deliver the active substance into the [...]
Nanorobot kills cancer cells in mice with hidden weapon
Researchers at Karolinska Institutet in Sweden have developed nanorobots that kill cancer cells in mice. The robot's weapon is hidden in a nanostructure and is exposed only in the tumor microenvironment, sparing healthy cells. [...]