Bacterial ATP synthase inhibitors – A novel approach toward antibiotics targeting difficult-to-treat Gram-positive and Gram-negative bacterial infections

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Challenge: Despite the availability of antibiotics, bacterial infections remain a major and growing health threat. Antibiotic resistance is a leading cause of deadly hospital-acquired infections worldwide. In 2017, the World Health Organization published a list of high-level threats bacteria for which new antibiotics are urgently needed. Among them, Staphylococcus aureus (SA) and its persistent forms, Methicillin-resistant SA (MRSA) and Pseudomonas aeruginosa (PA), among others, have been shown to have deleterious effects in patients that suffer from cystic fibrosis, chronic wounds or infections following orthopedic surgeries. New classes of drugs not susceptible to the mechanisms of resistance currently shared among bacteria are thus needed.

Solution: The team recently showed that tomatidine, a steroidal alkaloid extracted from tomatoes, possesses potent antibacterial activity against the persistent form of SA. Indeed, tomatidine inhibits a bacterial enzyme, ATP synthase, a clinically validated target. The team aims to optimize ATP synthase inhibitors using medicinal chemistry, microbiology, advanced structural and molecular modeling tools. The antibiotic activity, pharmacokinetics and pharmacology profile of these inhibitors will be investigated in vitro. The team will also perform proof of concepts in animal models for three major underserved indications, including MRSA-PA pulmonary co-infections in the context of cystic fibrosis, difficult-to-treat Gram-positive and Gram-negative infections and septicemia, and orthopedic biofilm-dependent infections.

Expected achievements/Impact: There is an unmet need for new antibiotics against antibiotic-resistant pathogens representing major threats to human health. This project aims to fully exploit bacterial ATPs as a target against difficult-to-treat bacterial infections. It will accelerate key development steps in lead optimization and generating critical data to identify a frontrunner compound as a candidate investigational drug. Once achieved, this project will also allow AmorChem Therapeutics to fulfill its long-term objective to bring commercial value to newly developed technologies.

Principal Investigators
Éric Marsault
François Malouin
University of Sherbrooke
Co-investigator
Martin Audet
University of Sherbrooke
Ongoing Project
$ 1,271,333 / 2 years
Supported by CQDM through:
– MEI
And by co-funding partner:
– AmorChem Therapeutics
– Cystic Fibrosis Canada
– Mitacs
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