Synthetic Antibiotics May Fight Drug-Resistant Superbugs

A decades-long scientific journey at Duke University has yielded a novel antibiotics method for combating gram-negative bacteria such as Salmonella, Pseudomonas, and E. coli, which cause many urinary tract infections (UTIs). In animal testing, the synthesized chemical works quickly and is long-lasting.

It operates by interfering with a bacterium’s ability to produce its exterior lipid layer, or skin.

“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 substance, known as LPC-233, is a tiny molecule that has been shown to disrupt outer membrane lipid production in every gram-negative bacterium tested. It killed all 285 bacterial types tested by co-authors from the University of Lille in France, including those that were highly resistant to market antibiotics.

And it works quickly. “LPC-233 has the ability to reduce bacterial viability 100,000-fold in four hours,” Zhou stated.

The molecule is also strong enough to make it all the way to the urinary system following oral delivery, making it a valuable tool in the fight against obstinate urinary tract infections (UTIs).

Tests run at high concentrations of the compound showed “exceedingly low rates of spontaneous resistance mutations in these bacteria,” according to a paper describing the findings, which appears Aug. 9 in Science Translational Medicine.

The chemical proved successful in animal trials when supplied orally, intravenously, or injected into the belly. The novel antibiotics saved mice from a potentially deadly dose of multidrug-resistant germs in one experiment.

Because of the specificity and safety requirements of the synthesized molecule, the search for this substance took decades.

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 required for gram-negative bacteria to produce outer membrane lipid.

Raetz became the chairman of biochemistry at Duke in 1993, after his work on this pathway at Merck & Co. failed to produce a viable clinical candidate. The Merck antibiotics was effective against E. coli, but it was not commercially feasible, therefore the pharmaceutical company abandoned 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.

Because of cardiovascular damage, the first human trial of LpxC inhibitors failed. The Duke group’s subsequent work focused on avoiding cardiovascular consequences while retaining the compound’s potency.

They tested almost 200 distinct versions of the enzyme inhibitor, continuously looking for improved safety and potency. Other compounds performed to varying degrees, but compound 233 was the clear 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.”

Zhou explained that the chemical operates in a remarkable two-step manner, which adds to its durability. After binding to LpxC, the enzyme-inhibitor complex changes shape slightly to become a more stable combination.

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.

Multiple patents have been filed on the family of chemicals, and Toone and Zhou have co-founded Valanbio Therapeutics, Inc., which is searching for partners to move LPC-233 through phase 1 clinical trials to examine 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.”

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