Many of the most important advances of modern medicine are under attack—their very value is being undermined by clever, tenacious infectious agents such as multidrug-resistant bacteria. That’s why our Infectious Disease team, led by Global Head Don Ganem out of Emeryville, CA, is committed to uncovering new and more effective ways to combat bacterial and viral infections.
“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,” says Ganem. “Think about chemotherapy: 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 immunosuppression: NIBR has an entire team focusing on organ transplantation, but the immunosuppressants those patients need make them targets for infection. So we have a dedicated program on viral infections of transplant recipients.”
Today, hospitals worldwide are particularly 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 antibiotics that overcome this resistance, largely due to the inherent scientific difficulties, 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 Portrait
Don Ganem, Global Head, Infectious Disease, 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 our modified antibiotics, which is more resistant to defensive bacterial enzymes than its predecessor, is expected to enter the clinic in 2016.
Aside from superbugs, the Infectious Disease team also focuses on serious viral infections, including respiratory viral infections. We also study opportunistic viruses that attack immunocompromised patients, such as transplant recipients, and serious chronic infections like hepatitis B. 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 that inhibit key viral enzymes. But down the road, 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 modulated. This work has already begun. “We’re in the early stage of research, but it has transformative potential.”
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