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Glaucoma Medication May Be Effective in Treatment of Tuberculosis, Even Drug-Resistant Forms; Effectiveness Revealed in Screening of 273,000 Compounds

A new discovery by Michigan State University (MSU) scientists suggests that a common medication used to treat glaucoma could also be used to treat tuberculosis (TB), even the drug-resistant forms. Dr. Robert Abramovitch, an MSU microbiologist, along with graduate student Benjamin Johnson, who helped lead the study, have discovered that ethoxzolamide, a sulfa-based compound found in many prescription glaucoma drugs, actually turns off the TB mycobacterium's ability to invade the immune system. The research paper was published in the August 2015 issue of Antimicrobial Agents and Chemotherapy. The article is titled “The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence.” "Basically, ethoxzolamide stops TB from deploying its weapons...shutting down its ability to grow inside certain white blood cells in the immune system," Dr. Abramovitch said. "We found the compound reduces disease symptoms in mice." According to Dr. Abramovitch, TB mycobacteria may not have eyes and ears, but they have an uncanny ability to sense certain environmental cues in the body and to adapt. One of these abilities is the organism’s ability to detect pH, which is key because particular acid levels indicate to the organism that it is being attacked by a host immune cell and prompt the organism to take effective counter-measures. "The compound we found inhibits TB's ability to detect acidic environments, effectively blindfolding the mycobacterium so it can't resist the immune system's assault," Dr. Abramovitch said. It's estimated that 2 billion people, globally, carry the TB infection, but in most cases it lies dormant and the immune system is able to prevent it from spreading through the body. "It's a standoff, however," Dr. Abramovitch said. "The immune system has difficulty clearing the infection and the TB mycobacterium is just waiting for the immune system to weaken."

Dr. Abramovitch and his research team screened 273,000 different compounds 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 Dr. Abramovitch developed earlier in his research, he eventually found the needle in the haystack that turned the mycobacterium's pH sensing ability off.

This elusive compound not only has the potential of preventing the disease from spreading, but Dr. Abramovitch suggests that it could help shorten the necessary length of treatment and thereby 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," Dr. 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, Dr. 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."

[Press release] [Antimicrobial Agents and Chemotherapy abstract]