The advances of modern medicine, including surgery, chemotherapy, and organ transplantation, have been made possible by our ability to control infections. But drug resistance has the potential to undermine these gains.
That’s why Infectious Diseases, led by Global Head Don Ganem in Emeryville, California, is committed to uncovering new and more effective ways to combat bacterial and viral infections.
“Think about chemotherapy,” says Ganem. “We can’t use chemotherapy drugs if we can’t rescue cancer patients from the infections these agents make them susceptible to. The same thing is true for organ transplantation – the immunosuppressants those patients need make them targets for infection.”
Today, hospitals worldwide are threatened by so-called “superbugs” — bacteria that have developed resistance mechanisms against even our strongest antibiotics. While many large pharmaceutical companies have abandoned the search for new antimicrobials, we are embracing the challenge.
“From a scientific point of view, there are two major hurdles,” says Ganem. “First, bacteria have had millions of years to evolve strong defenses.” For instance, they have strong armor in the form of poorly permeable outer membranes. And the few drugs that get across this armor are often immediately escorted back out by efflux pumps or inactivated by modifying enzymes inside the bug.
Many of the medical advances we rely on also make people susceptible to infection, so we must be able to deal with that in order to realize their benefits.
“Another problem is that many of the molecules that make up our standard chemical libraries are optimized for getting into human cells rather than bacterial cells,” says Ganem, referring to the large libraries used to screen for potential new drugs. “So we may not have the best starting materials.”
Don Ganem, Global Head of Infectious Diseases at the Novartis Institutes for BioMedical Research
We are looking to get around bacteria’s varied defenses through both the modification of existing antibiotics and the use of wholly new chemical entities. One of these compounds – an updated monobactam antibiotic that is more resistant to defensive bacterial enzymes than its predecessor – is currently being tested in clinical trials.
The Infectious Disease team also focuses on serious viral infections, including hepatitis B, respiratory viruses, and opportunistic infections that attack immunocompromised patients. Here, a new set of scientific challenges arises.
“In virology, the issues are different,” explains Ganem. “Since viruses grow in human cells, our chemical libraries contain many molecules appropriate for getting to their viral targets. But each virus requires a specific therapy molded to its specific biology. We need to decide what are the most important infections and the best biochemical targets inside of each.”
Current programs are looking at small molecules and antibodies that inhibit key viral proteins. But in the future, Ganem predicts a shift for his team. “If I imagine what our next generation of antivirals will look like, I think they will modulate our immune response.” He envisions approaches that are analogous to cancer immunotherapies, in which the human immune system is activated or manipulated. This work has already begun. “We’re in the early stage of research, but it has transformative potential.”
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