Novel 'fast, tenacious' molecule can KO drug-resistant superbugs
Decades of work has seemingly paid off with scientists developing a potent new synthetic molecule that swiftly knocked out 285 strains of bacteria it was tested on, setting it up as a valuable ally in our fight against a looming superbug infection crisis.
It’s not the first modern breakthrough in synthetic antibiotics, with a lot of research now laser-focused on finding new ways to tackle often deadly bacteria that’s increasingly circumventing our longstanding traditional drugs.
This new molecule works by disrupting the bacterium’s ability to form an outer lipid layer, both killing the pathogen and rendering it unable to multiply – a stress response that can be triggered by antibiotics resistance, making infections much more difficult to treat.
“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 in the Duke School of Medicine. “Our compound is very good and very potent.”
The compound, LPC-233, messed with lipid formation in every gram-negative bacterium it was tested on. Among the 285 bacterial strains it was pitted against, including some with high antibiotics resistance, it killed them all efficiently and quickly.
“LPC-233 can reduce bacterial viability by 100,000-fold within four hours,” Zhou said.
While all tests have so far been on mice models, it was successful when administered orally, intravenously and injected into the abdomen. LPC-233 was also able to target what would have normally been a fatal dose of multidrug-resistant bacteria, perhaps the hardest ‘superbug’ to defeat with current medical intervention.
While Zhou has been working on this breakthrough for years, credit should also go to his late colleague, Christian Raetz, former Duke biochemistry chair, highlighting how few science discoveries happen overnight. Incidentally, LPC-233 got its name because the team had tried, failed and improved on the molecule some 232 times before landing on what they were after.
“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.”
LPC-233 targets the LpxC enzyme, which is on the “Raetz pathway.” Earlier developments targeting LpxC resulted in cardiovascular toxicity in human trials.
“We realized that we could tweak the compound to make it better,” Zhou said of his work, initially with Raetz and then alongside Duke chemistry professor Eric Toone. “It fits in the right way to inhibit formation of the lipid. We’re jamming the system."
What’s more, after the compound binds to LpxC, it changes its shape to become an even more stable complex. Importantly, this gives it the stability to outlive the lifespan of 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.”
In December 2022, the World Health Organization sounded the alarm on how quickly antibiotic-resistant bacteria are adapting to current drugs and how critically important it is to develop new ways to fight these bugs.
The scientists have now patented LPC-233 and some other compounds and have established a startup to develop the drug. That company, ValenBio Therapeutics, is now planning phase 1 clinical trials to test LPC-233 safety and efficacy in humans.
The research was published in the journal Science Translational Medicine.
Source: Duke University