Pharmacy professor lands $3.6 million grant to develop phages cocktail to fight bacteria

BUFFALO, N.Y. — While working on dual doctoral degrees in pharmacy and pharmaceutical sciences at the University at Buffalo, Nicholas Smith, PharmD, PhD, was intrigued by how multiple drugs could be combined to treat drug-resistant infections.

His interest was partially prompted by the alarming state of antimicrobial resistance, which the World Health Organization and others report could result in 10 million deaths and an additional $1 trillion in health care costs by 2050.

“I started to think about what the next frontier could look like and what direction the field was moving in,” said Smith, now an assistant professor of pharmacy practice in UB’s School of Pharmacy and Pharmaceutical Sciences. “Bacteriophages, or phages, seem really interesting, and I thought maybe they could be one of the next things.”

Smith’s curiosity and deep dive into phages, a type of virus that infects and replicates within bacteria, has paid off. He was just awarded a five-year, $3.6 million research grant from the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health, for his project, “Pharmacokinetics and Pharmacodynamics of Mechanistically Aware Phage Cocktails.”

“As we face the growing threat of antimicrobial resistance, discovering new ways to combat drug-resistant infections is essential,” said Gary Pollack, PhD, dean of the pharmacy school. “Dr. Smith and his team’s work in developing effective phage-based therapies plays a vital role in reducing the impact of antibiotic resistant pathogens and addressing a critical public health challenge.”

Smith is collaborating with Dwayne Roach, PhD, associate professor of biology at San Diego State University, who is an expert in phages research. Co-investigators at UB are Liang Chen, MD, PhD, professor of pharmacy practice, Gene Morse, PharmD, SUNY Distinguished Professor of pharmacy practice, and Troy Wood, PhD, professor of chemistry. Together, they are working with Smith to identify the best strategy to combine multiple phages into a cocktail.

More targeted, less harmful

Phages are promising, Smith said, because they target bacteria very precisely and can be less harmful to human cells, which they do not infect. However, their use so far has primarily been experimental.

“Researchers have not found a standard way to use these phages effectively,” Smith said. “There are many unanswered questions as to how phages work in the body, especially how to dose them the most effectively.”

Over the next five years, Smith and his team, which also includes several pharmacy students, will investigate how phages distribute throughout the body to the site of infection and how effective phages are in resolving infections once there.

Century-old virus

Phages are nothing new — they were actually discovered in the early 20^th century. Phages were overlooked, Smith noted, because other weapons to combat bacteria, such as penicillin, were highly effective and more predictable.

“Now, that we’re facing all this resistance to antibiotics, the research community has started to revisit phages as a potential alternative,” he said. “In our study, we’re trying to apply a lot of the tools for drug development that have come into existence since phages were originally discovered.”

Currently, phages are predominately administered only in compassionate use circumstances — for patients who would likely die without treatment and for whom there are no other options, Smith said. This is usually due to antibiotic resistance, drug allergy or toxicity to other last-line agents. Smith and his team are taking phages that have demonstrated clinical success in these cases to determine how much phages are distributed throughout the body to get to the right dose.

“When you talk about antibiotic resistance, you have to think about who specifically it affects,” Smith said. “It’s often patients with COPD (chronic obstructive pulmonary disease) or cystic fibrosis or who are immunosuppressed while getting treatments for cancer. These infections really can distract from other treatments that they’re currently under for the conditions that they have.”

Using computer modeling

The first phase of the research, which has already begun, is determining how to pick individual phages and how to combine them for optimum results. The second and third phases will be devoted to developing the cocktails and testing optimal phage combinations. The final phase is setting up the infrastructure for future human trials.

He explained that they will use in vitro assays that they’ve developed, along with some computer model-based approaches, to figure out how to best dose the phages and if one phage can affect the efficacy of another.

“If you’re trying to dose one phage, that’s less of a problem,” he said. “But if you’re talking about a family of five phages, then the number of permutations of that explodes quite quickly into a problem that’s very difficult to solve using just 100% wet bench type preclinical research tools. So, we have to mix wet bench research with these computational tools to help us make sense of that data, sift through it and help simplify the problem.”

Smith said he feels honored to have the opportunity to conduct this crucial research and to work with a talented research team to move toward his ultimate goal of creating highly effective phage-based therapies.

“The urgency of finding new ways to combat drug-resistant infections, especially for our most vulnerable patients, drives everyone on the team,” he said. “The potential to realize the longstanding promise of phage therapy as precise and effective treatment is incredibly exciting for everyone involved.”

Other members of the research team include Thomas Nguyen, PharmD and current PhD candidate; Brian Ho, PharmD, Jacob Sanborn, BS, and pharmacy graduate students Leeha Mahmood, Jingxiu (Angela) Jin, Karishma Patel, Liem Nguyen, Yan Pan, Haniya Alam and Claire Han.