Stony Brook team in search of cure for infectious bugs

Nearly 100 years after penicillin’s discovery, antibiotics have reached a critical crossroads: Their abuse, misuse and overuse have tarnished the promise they once held as miracle drugs, pushing the world closer to an era without cures, several studies show.

Medical researchers nationwide are racing to develop ways to treat bacterial infections, even as some observers wonder if they will keep pace with the bugs. And unless new drugs are developed, the worldwide death toll from infections once cured by penicillin could reach into the millions by 2050, according to predictions from the World Health Organization.

On Long Island, a team at Stony Brook University School of Medicine has taken up the challenge, working on dual fronts. Dr. David Thanassi and colleagues are collaborating with researchers at the Van Andel Institute in Michigan on a series of studies to better understand how bacteria cause infection.

For the past five years, they also have been developing an experimental therapeutic dubbed an anti-infective, abandoning the term antibiotic. The different name, Thanassi said, signals a novel method of combating infectious bugs.

Thanassi, chairman of molecular genetics and microbiology at the medical school, and his colleagues aren’t trying to kill bacteria as antibiotics do. They have taken aim at disabling a key appendage of bacteria — paralyzing their ability to maneuver.

Thanassi's team is looking specifically at E. coli bacteria because of the role it plays in a high number of urinary tract infections, which are both costly to treat and usually bounce back in a more aggressive reinfection. On E. coli's surface are hairlike appendages called pili that initiate the infection process. 

“We are targeting the virulence mechanism,” Thanassi said of the pili.

E. coli, and countless other bacteria, use tiny tentacles on their surfaces to adhere to tissue. Once fully adhered, the bacteria are free to invade.

“A lot of our focus has been on understanding the steps E. coli uses to assemble these structures,” Thanassi said of the pili. “We also know that targeting and disrupting the pili can be an alternative approach to conventional antibiotics.”

Knowing E. coli needs its hairy tentacles to cause UTIs, Thanassi and his colleagues are studying an experimental therapeutic, the anti-infective, to disable E. coli’s ability to adhere to the bladder wall and other regions of the urinary tract.

If the bugs can’t stick, they can’t infect, Thanassi said of his anti-infective, which he hopes ultimately will be tested in a clinical trial. “In a bladder full of urine they’ll be washed out, and in theory, would not promote antibiotic resistance,” he said. 

New methods of addressing UTIs would be a boon for patients in hospitals and nursing homes who have had to rely on urinary catheters.

“These infections are often treated with broad-spectrum antibiotics,” said Huilin Li, Thanassi’s collaborator at the Van Andel Institute.

“Despite their importance as a medical tool,” Li said of antibiotics, “they are increasingly problematic due to their potential to cause drug resistance and their tendency to disrupt the body’s [healthy] microbial balance.”

The WHO has said that if new treatments are not created, deaths from bacteria will rise from 700,000 a year worldwide to about 10 million annually by 2050, outstripping the number of cancer deaths each year. 

In Washington, D.C., Wes Kim of Pew Charitable Trust‘s Antibiotic Resistance Project painted a complex portrait of the drug development pipeline for bacterial infections and the escalating resistance crisis.

Because of low profit margins, some pharmaceutical and biotechnology companies have bailed on new antibiotics, said Kim, who counted one major pharmaceutical company and two biotechs having abandoned antibiotic research in recent months. Other giant drugmakers left antibiotic development years ago, leaving doctors, in some cases, without enough choices for patients with infections.

“Unfortunately, they are not coming back at this time,” Kim said. “Most recently Novartis closed down its antibiotic discovery team. And what is even more sad, it was one of the few pharmaceutical companies that had invested in basic [antibiotic] research. So that was a huge loss.”

Besides pharmaceutical companies leaving antibiotic research, Kim said, there have been decades of misuse and overuse of the ones that exist. Patients have demanded them for viral infections, which antibiotics can't treat. The agricultural industry has used them to fatten livestock headed for slaughter. 

Fewer than 100 nontraditional methods of fighting bacteria, such as Thanassi's, are under development, a number that pales in comparison to the thousands of medications being researched for various forms of cancer, he said.

Venture capital money also is directed more toward cancer and less in the direction of infectious diseases, Kim added, and antibiotics’ low pricetags have proved to be another turnoff.

“They’re so cheap, you can buy a full course [of treatment] for only $5 at CVS,” Kim said.

At Stony Brook, Thanassi and his team are committed to learn more about how E. coli uses its hairy tentacles to initiate infection — even employing an advanced form of imaging to view the appendages up close. He remains convinced that conventional antibiotics aren’t the only way to treat bad bugs.

“Our findings open the door to new therapies targeting bacterial pili, and related virulence factors, as an alternative to traditional antibiotics,” Thanassi said.