A medication commonly used to treat glaucoma could also be used to treat tuberculosis, even in drug-resistant form, a new finding by Michigan State University scientists suggests.
The discovery that ethoxzolamide, a sulfa-based compound found in many prescription glaucoma drugs, actually turns off the bacterium’s ability to invade the immune system, was made by Robert Abramovitch, an MSU microbiologist, along with graduate student Benjamin Johnson who helped lead the study.
“Basically, ethoxzolamide stops TB from deploying its weapons…shutting down its ability to grow inside certain white blood cells in the immune system,” Abramovitch said. “We found the compound reduces disease symptoms in mice.“
TB may not have eyes and ears, according to Abramovitch, but it does have the strange ability to sense certain environmental cues in the body and adapt. Those cues include the infection’s ability to detect pH, or acidity levels, which tells the disease it’s being attacked by a host immune cell.
“The compound we found inhibits TB’s ability to detect acidic environments, effectively blindfolding the bacterium so it can’t resist the immune system’s assault,” Abramovitch said.
It’s estimated that 2 billion people, globally, carry the infection. In the majority of cases it lies dormant and the immune system is able to prevent it from spreading in the body.
“It’s a standoff however,” he said. “The immune system has difficulty clearing the infection and the TB bacterium is just waiting for the immune system to weaken.“
273,000 different compounds were screened by Abramovitch and his research team, in hopes of finding one that could possibly stop the disease. By using a synthetic biosensor that glows green in response to conditions that mimic TB infection, something he developed earlier in his research, he eventually found the needle in the haystack that turned the bacterium’s sensing ability off.
Still, this hard to find compound not only has the potential of preventing the disease from spreading, but Abramovitch suggests that it could help shorten the length of treatment and slow the emergence of drug resistance, particularly if found to work in conjunction with other existing TB drugs. Current treatments can last up to six months.
“The single biggest reason for the evolution of drug-resistant strains is the long course of treatment,” Abramovitch said. “It’s difficult for a patient to complete the entire antibiotic course required to kill all of the bacteria. Shortening the duration will help slow the development of these resistant strains.“
Trying to kill TB bacteria isn’t the only way of stopping the disease though, Abramovitch added.
“We don’t necessarily have to find drugs that kill TB, we just need to find ones that interfere with the bug’s ability to sense and resist the immune system. By giving the immune system a helping hand, natural defenses can then kill the bacteria.“
Benjamin K. Johnson, Christopher J. Colvin, David B. Needle, Felix Mba Medie, Patricia A. DiGiuseppe Champion, and Robert B. Abramovitch The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence Antimicrob. Agents Chemother. August 2015 ; 59:8 4436-4445 doi:10.1128/AAC.00719-15
Illustration: Wellcome Images