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Defending against antibiotic resistant bacteria
UMass researchers and industry partner to research new molecules that would protect immune system cells from antibiotic resistant bacteria, funded by a $600,000 NIH award.
October 5, 2020
Associate professor Alejandro Heuck’sbiochemistry lab, in collaboration with Worcester-based Microbiotix, Inc., has been awarded a two-year, $600,000 NIH Small Business Technology Transfer award to develop a high-throughput screening method to identify inhibitors of a bacterial secretion system that attacks human cells by injecting toxins. A treatment based on the inhibitors could act by a new mechanism to enhance the host’s innate immune response to infection, Heuck says.
His co-principal investigator on the project is Donald Moir, chief scientific officer at Microbiotix, who has many years of experience in anti-infective drug discovery and inhibitors of Type 3-mediated secretion. Heuck himself is an expert in Type 3 secretion-mediated translocation, the assembly of the translocon and its function.
As he explains, “Bacterial Type 3 secretion systems act like weapons to kill our white blood cells. When our immune system macrophage cells attempt to destroy the intruders, the bacteria use these weapons like syringes to inject toxins to kill the macrophages. We’re trying to identify small molecules that block the injection of the bacterial toxins to prevent them from killing macrophages.”
The new molecules would be used in combination with antibiotics, he adds. With this method, after the antibiotics wipe out as many of the bacteria as possible, the small molecules would be in place to protect the body’s own immune cells against the injected bacterial toxins. The macrophages would kill the remaining antibiotic-resistant bacteria.
Heuck explains, “Sometimes antibiotics don’t kill all the bacteria, some of them survive because of resistance. But when we protect the macrophages from the bacterial attack, the immune system can kill the few bacteria that survive the antibiotics.”
The researchers plan to first design the new approach to better control the pathogen Pseudomonas aeruginosa, which is classified as a serious threat by the Centers for Disease Control. Nearly 30% of pathogens isolated in hospitals are resistant to three classes of antibiotics.
The Heuck lab’s collaboration with Microbiotix began two years ago after Heuck and colleagues published a manuscript that triggered the new idea. The lab won initial support in a translational midigrant from the campus’s Institute for Life Sciences Models to Medicine (M2M) Center, funds from the College of Natural Sciences’ Bridge and Seed Funding program and, more recently, a UMass Faculty Research Grant/Healey Endowment Grant. These allowed the researchers to collect the preliminary data required to move the idea forward toward the NIH grant.
Heuck says, “Basic research – us alone in the lab – sometimes leads to an idea that could benefit the public but we don’t have the tools or expertise to go to the next step like a company has. I really appreciate that the university has so many mechanisms to help us reach out and make these connections. When university researchers join forces with local small companies, we accelerate the creation of life-saving technologies and stimulate the economic growth of the local industry.”
He adds that discovery of a lead inhibitor chemical series will provide “a compelling basis to obtain additional funding to develop such lead series into a preclinical candidate, and ultimately obtain a novel drug against multi-drug resistant P. aeruginosa.”
At a more advanced stage, he plans to seek research partnerships or venture financing to develop the product through clinical proof-of-concept, or Phase 2. “Once the clinical proof-of-concept is demonstrated, a corporate partner will be sought for expanded clinical trials and eventual commercialization,” Heuck says.