At any moment, about a third of the world's population is infected with tuberculosis (TB). Most is inactive, latent TB; however, active TB still kills more than one million people each year. Increased urbanization, public health complacency, and immunity-weakening HIV have enabled the spread of TB in recent decades. Some strains are now extensively drug-resistant, virtually untreatable, and usually fatal.
But an international team led by scientists at The Scripps Research Institute (TSRI), the Howard Hughes Medical Institute, and the Albert Einstein College of Medicine of Yeshiva University has identified a promising new anti-tuberculosis compound that killed more than 99.9% of highly drug resistant strains within three weeks.
"These findings represent an effort to help solve one of the major global health crises of our time—the resurgence of TB and its dangerous drug-resistant strains," said Peter G. Schultz, the Scripps Family Chair Professor of Chemistry at TSRI, who was senior author of the study with William R. Jacobs, Jr., a member of the Howard Hughes Medical Institute and professor of microbiology & immunology and genetics at Albert Einstein College of Medicine.
Professor Peter G. Schultz
Although the two leading TB drugs, isoniazid and rifampin, have been in use since the 1950s and 1960s, new TB infections still occur at a rate of roughly one per second. The bacterium that causes TB – Mycobacterium tuberculosis (Mtb) – frequently reverts to a dormant, non-replicating state and also creates attack-resistant cell colonies called biofilms, which contain a high proportion of non-replicating TB. This makes TB unusually well adapted to persisting in humans because these other forms of TB are much less susceptible to existing drugs. Effective TB therapy thus requires months to years of regular medication, and many patients quit before completing the treatment, ultimately incubating drug-resistant TB strains.
The research team set up a screening test to detect compounds that block TB's ability to form these attack-resistant biofilms. Screening a diverse library of 70,000 compounds, the scientists quickly identified one, dubbed TCA1. "In cell cultures and in mice, this compound showed powerful activity against ordinary active TB bacteria, non-replicating TB bacteria, and even extensively drug-resistant TB strains," said Feng Wang, a member of the Schultz lab at TSRI and first author of the study with Dhinakaran Sambandan of the Jacobs lab and Rajkumar Halder of the Schultz lab.
In cell culture tests, TCA1 on its own killed more than 99.9% of ordinary, actively replicating TB bacteria within three weeks, and, in combination with isoniazid or rifampin, killed 100% within that period. TCA1 also proved effective against drug-resistant strains, removing all signs of one common strain within a week when combined with isoniazid. Against a highly fatal "super-bug" strain from South Africa, which resists all conventional TB drugs, the new compound had a kill rate of more than 99.999% within three weeks.
As expected, TCA1 also showed potent effects against non-replicating TB, and tests in mice suggested that the combination of TCA1 and isoniazid could be more powerful than existing drug regimens. The compound works in a unique way by targeting two enzymes, one for the active stage and another for the dormant stage. "I don't know of any other antibiotic that kills replicating bacteria through one pathway and non-replicating bacteria through another, as this one does," said Dr. Wang.
TCA1 showed no sign of toxicity or adverse side effects, and also showed almost no tendency to induce drug resistance in TB. Assuming preclinical tests are completed successfully, the group hopes to find a pharmaceutical company partner to sponsor clinical trials.