Mayland Chang of the Department of Chemistry and Biochemistry at the University of Notre Dame has received a five-year, $5.5-million grant from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases to conduct translational research aimed at the discovery and development of drugs to fight serious gram-positive bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA).
The award, significantly greater than typical grants at the research level, required a product development plan for moving a compound towards commercialization in addition to the usual scientific plan.
Large pharmaceutical companies no longer invest in basic and translational research on antibiotics as they once did in their laboratories. The return on investment for such drugs, used by patients only occasionally and briefly because they actually cure the disease, is far less than potential returns from drugs required for managing chronic conditions, such as high blood pressure or high cholesterol. While drug development and clinical trials typically costs more than $1 billion, antibiotics typically return only $200 million to $300 million a year for each illness they treat.
“The easy picks have already been found,” Chang says. “It is harder to come up with a new template, one you can still protect with patents. By the time the compound makes it to the market, in a couple of years or so, you’re going to have a resistance problem. Bacteria are going to mutate, and they are going to develop resistance to any antibiotic. Because there are no financial incentives for large pharmaceutical companies to do this, it’s a big problem. You need other mechanisms to address this unmet medical need.”
Chang has already developed a lead template for the new class of compounds and started the process of optimizing its pharmaceutical properties, such as solubility, efficacy, pharmacokinetics and dosage requirements.
“You’ll always need some new classes of compounds to combat resistance,” she says. “The NIH recognizes that something else needs to be done for these serious bacterial infections and other diseases like tuberculosis.”
With the grant, Chang’s multidisciplinary research team will design and synthesize variations of the compound, impart drug-like properties, and test them for antibacterial activity in animal models of infection, continuing work they have already started. The team includes Chang, Shahriar Mobashery, Sergei Vakulenko, Mark Suckow, all of Notre Dame; and Juan Hermoso of Consejo Superior de Investigaciones Científicas, Madrid, Spain.
“We’re very hopeful and optimistic that we’ll come up with a compound that we can take into preclinical development and ultimately into clinical trials,” Chang says. “I think we have a very good opportunity here at Notre Dame in terms of the critical mass in drug discovery. We can do everything from the computational aspects to synthesis to imparting drug-like properties. We can test these in vitro against different kinds of bacteria and take these into animals to optimize the pharmacokinetics and to be able to test in animal models of infections. Many other academic places cannot do this.”
The risk of dead-end research is highest at the beginning of a project. Of 10,000 compounds discovered, 250 make it to preclinical development, and five reach clinical trials. The more the potential drug is developed, weeding out failed attempts through in vitro methodologies and animal testing to identify compounds for clinical trials, the more attractive it becomes to large pharmaceutical companies that are willing to partner with the researcher or purchase the compound for preclinical development and clinical trials.
Early results suggest that Chang’s lead antibiotic shows comparable results to linezolid, marketed as Zyvox, which is the “drug of last resort” on the market for treating MRSA and vancomycin-resistant Enterococci (VRE). Unlike linezolid, which prevents bacterial growth, the compound kills bacteria. Linezolid has sales of some $1.1 billion a year, but bacterial resistance to the 10-year-old drug is expected to grow.
_*Contact*: Mayland Chang, professional specialist, chemistry and biochemistry, 574-631-2965, mchang@nd.edu