Researchers to test blocking ‘hypermutations’ in deadly bacteria

To combat “hypermutated” strains of deadly, antibiotic-resistant bacteria, the National Institute of Allergy and Infectious Diseases has awarded UB a $4 million grant to study the underlying mechanisms by which rapidly acquired mutations interfere with antimicrobial therapies and develop new treatment strategies to combat these deadly infections.

The five-year study, funded by the agency’s Research Project Grant (RO1) program, will focus on antibiotic-resistant strains of Pseudomonas aeruginosa, which, in 2017, caused an estimated 32,600 infections among hospitalized patients and 2,700 deaths in the United States, according to the Centers for Disease Control and Prevention.

The investigation is led by Brian Tsuji, professor of pharmacy practice and associate dean of clinical and translational sciences, School of Pharmacy and Pharmaceutical Sciences, and Mark Sutton, professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB. The award is the largest R01 grant awarded to UB by the National Institutes of Health in 2022.

“Pseudomonas aeruginosa is an urgent, global, public health threat. Highly resistant strains have emerged that possess a remarkable evolutionary capacity to adapt and persist in the face of therapy,” says Tsuji. “The scarcity of treatment options and the broken antibiotic pipeline demands the development of new therapeutic strategies that target nontraditional, unexploited pathways.”

Sutton says the study’s results “will set the cornerstone for future testing of anti-mutators in clinical trials and provide unprecedented insight into combination therapies for bacterial strains that are urgent threats.”

“There is mounting evidence that ‘hypermutator’ strains, which have a significantly increased frequency of spontaneous mutations, may help bacteria to develop antibiotic resistance and become more pathogenic,” he says.

These mutations in the bacteria develop when errors occur during DNA replication and repair.

Tsuji and Sutton aim to define the contributions of hypermutators to antibiotic resistance. In collaboration with Anthony Berdis, professor of chemistry at Cleveland State University who previously pioneered the synthesis and testing of non-natural nucleotides as anti-cancer therapies, the researchers also aim to develop new treatment strategies for antibiotic-resistant strains of Pseudomonas aeruginosa by combining the delivery of antibiotics with non-natural nucleotides.

Co-investigators Thomas Russo, SUNY Distinguished Professor of Medicine and chief of the Division of Infectious Diseases at the Jacobs School, and Nicholas Smith, UB assistant professor of pharmacy practice, played a key role developing the grant application.

Jan Kaur, research scientist; Katie Rose Boissonneault, research scientist; Jack Klem, PharmD student; Patricia Holden, senior research scientist; and Raymond Cha, clinical associate professor of pharmacy practice, all in the School of Pharmacy and Pharmaceutical Sciences, generated the critical preliminary data that served as a catalyst for the application.

The early stages of the project, including establishing the research team, were supported by the UB Genome, Environment and Microbiome (GEM) Community of Excellence.

“GEM provided the seed funding to build new bridges so that our R01 could be a leading example of team science at UB and across the U.S.,” says Sutton.

Adds Tsuji: “I am so grateful to our incredible team of interdisciplinary scientists, students and investigators who had to think outside of the box to propose new strategies to combat resistance. Without them, none of this would be possible. They deserve all the credit.”