A Home Away from Home

A HOME AWAY FROM HOME

Dr. Scott Franzblau and his ITR team are like a family of researchers, and they wouldn’t have it any other way.

JUST PAST A STANDARD SET OF SECURE hospital-style double doors on the north end of the UIC College of Pharmacy’s fourth floor lies a clean, white hallway that runs straight through the middle of the Institute for Tuberculosis Research (ITR). Several doors, many with small windows, line its walls, punctuated by scientific posters and large picture windows lending views into various spaces that researchers enter and exit, where platform shakers quietly agitate flasks and colleagues convene to discuss their work. While still in the midst of a global pandemic—ironically, the sandbox in which the institute plays—much of this 5,500 square feet of space is likely not as busy as it was before the quarantine of 2020. Still, behind many doors are a number of faces found.

And their eyes, betraying what is hidden beneath surgical masks, belong to smiling faces.

Because, while the ITR is a lab, and a very serious one at that, where considerably grave and life-changing work is done, it is also a sort of home away from home. A familial place where discoveries, careers, and personal and professional relationships are born and thrive. And where some of the brightest minds in their fields gather to work on eradicating a relentless killer that has plagued humanity since ancient times, sickening 1.2 million children each year and claiming 3,836 lives around the globe each day, according to the TB Alliance. At the helm of this great and humble vessel is Dr. Scott Franzblau, ITR director and Albert Schatz Professor of Medicinal Chemistry and Pharmacognosy.

Originally from a small suburb of New York City on the other side of the Hudson River, Franzblau dreamed of living in open spaces, swearing never to reside east of the Rocky Mountains after spending his postgraduate years in Arizona and the Pacific Northwest.

“I was an idealist,” he admits, almost ruefully. “I wanted to save the world. When I finished my PhD, I thought, ‘What are the most neglected infectious diseases in the world that nobody’s working on?’ My priority was to try to do something that would benefit humankind in the only area where I thought I had any competence, which was microbiology.”

At the time, his directive led him to the National Hansen’s Disease (Leprosy) Program in Carville, Louisiana, where he spent 17 years seeking a cure for leprosy until the mid-1980s when a multidrug-resistant strain of TB began surfacing in the United States among immunocompromised HIV patients.

Then he got a call from the NIH, which was aware that Franzblau had one of the few biosafety level-3 (BSL-3) labs in the nation at his facility, giving him the capability to work with TB. That kicked off a partnership that lasted for the next decade, screening compounds against TB for the NIH. At the same time, his work with leprosy came to completion.

This is a place where you can go from discovery at the bench to clinical trials without ever leaving the campus.

“From there on, it was one-hundred percent TB. No looking back.”

“The person who convinced me to stay was Larry Danziger,” he recalls. “He told me, ‘This is a place where you can go from discovery at the bench to clinical trials without ever leaving the campus. Everything you need is here.’

“That’s what I wanted. I wanted to do new drug discovery.”

In the past 20-plus years since his arrival, Franzblau has successfully built his own drug discovery ensemble with players in the college from medicinal chemistry, natural products chemistry, microbiology, drug metabolism, pharmacokinetics, and toxicology, all focused on natural products-related drug discovery for TB. Indeed, the discovery of drugs—three compounds in development by the Global Alliance for TB Drug Development for which the ITR contributed IND-supporting data are either in or about to enter phase I trials—is among one of the major contributions Franzblau lists among the ITR’s accomplishments. Another is the development of a high-throughput compatible assays that can quickly determine if a compound is capable of killing TB.

“We’ve been able to assist people throughout the world in testing their compounds against TB,” says Franzblau. The ITR is also in the throes of a research project with the TB Alliance to produce new clinical-stage drug candidates for treating TB. The five-year effort is funded by the National Institute of Allergy and Infectious Diseases–supported Centers of Excellence for Translational Research (CETR). ITR is one of three partners with TB Alliance, the primary recipient of the grant.

As part of the project, the ITR is receiving up to $9 million in funding to investigate promising natural compounds and their effect against TB and to evaluate the treatment potential of compounds developed by researchers from Harvard University and Johns Hopkins University, the other key partners on the project.

“We discovered a class of compounds that hit a new molecular target in TB,” says Franzblau. “But what’s interesting is that the original compounds we found that led us to this target are natural products.”

The original compounds Franzblau refers to aren’t exactly new discoveries but more like an upcycle of the previously tested material.

“Twenty years ago, people stopped screening big microbial libraries that were built by pharmaceutical companies . . . who fermented thousands of microbes looking for new antibiotics,” says Franzblau.

In the past, testing compounds against TB was unpopular. It was dangerous to work with and grew slowly compared to other bacterial pathogens, he explains. He believes that some of these compounds may have been overlooked simply because they weren’t tested against TB.

“My thinking was, probably a lot of things [may have] only killed TB and nothing else, so, not seeing activity against E. coli or Staphylococcus or Bacillus, they said, ‘Let’s get rid of that,’ which is typically what happens in these big screening programs. So we thought it would be prudent to try to get these big microbial collections and screen directly against virulent microbial TB.”

Thanks to Sang Hyun Cho, research associate professor of medicinal chemistry and associate director of the ITR, who came across an intact, living library of microbes at Myongji University in South Korea, the ITR has been able to screen more than 200,000 actinomycete fermentation extracts.

“After about 65,000, we got our first hit,” recalls Franzblau. Ecumicin, named after the collection in which it was found—the Extract Collection of Useful Microorganisms (ECUM)—has shown activity in TBinfected mice and is currently the subject of efforts to improve oral bioavailability.

“This project is moving along really well,” he says. “We’re really excited. We’ve ended up with two different related classes of compounds that hit the molecular target.”

Five years ago, the ITR expanded their work to include other infectious agents, including Borrelia burgdorferi, which causes Lyme disease; ESKAPE gram-negative and gram-positive bacteria that are troublesome because of their drug resistance; and nontuberculous mycobacteria (NTM), which are related to TB but are arguably more difficult to treat because of their resistance to most types of antibiotics.

Their work currently focuses on two nontuberculosis mycobacteria, Mycobacterium avium and Mycobacterium abcessus, which cause opportunistic infections, particularly in patients with cystic fibrosis. Franzblau says they have now added a third NTM, Mycobacterium ulcerans, the culprit behind Buruli ulcer, a disease geographically restricted to equatorial regions that causes severe skin ulcerations.

The ITR has also begun building their own microbial library from what Franzblau believes are unexplored sources: activated sludge from wastewater treatment plants—an idea he came up with sitting in a microbial ecology course as an undergrad at Rutgers—and the surfaces and habitats of birds, an idea contributed by Jonathan Bisson, a research assistant professor in the Department of Pharmaceutical Sciences who oversees the isolation and identification of active compounds from these new sources.

“M. avium was originally isolated from birds, so there may also be bacteria that might keep them in check [on birds].”

Franzblau believes the ITR’s success, before all else, is due to its “high quality, dedicated personnel at every level.

“After 20 years at UIC, I am still impressed by the competence and dedication of more than 90 percent of all of those we have hired over this time.”

For many ITR employees, the feeling is mutual.

“The strive for excellence starts from Scott,” says research professor Larry Klein, “and carries through to the many diverse colleagues, access to state-of-theart equipment, and the open research and learning environment adopted by Scott.”

P3 Jeffrey Yoshihara has worked as a graduate research assistant at ITR since his P1 year. He values having learned about the arduous process of bringing a drug to market. “The work I have done is a mere snapshot of the bigger picture of drug discovery against TB, and it makes me feel as if I am fighting for something bigger than myself.”

Mallique Qader, a postdoctoral research associate, considers the training he’s received while “being a part of the ITR family” as “priceless . . . both rewarding and eye-opening.”

“I wish, for as long as I can, to be involved in this research,” says senior research scientist Farah Movahed Zadeh. “Doing this work is to love life, and it makes life itself full of meaning.”