Science Codex (06.17.2013)
Researchers from the Scripps Research Institute (TSRI), Howard Hughes Medical Institute, and Albert Einstein College of Medicine of Yeshiva University have discovered a promising new anti-TB compound that can fight TB bacteria in two ways. The researchers were searching for a drug that cleared TB infection quickly and was effective against replicating and nonreplicating TB infection.
Feng Wang, of the Schultz laboratory at TSRI and first author of the study, created a screening test to detect compounds that block TB’s persistence-related ability to form biofilms. He used a related, but nondisease-causing mycobacterium for the high-throughput test. After screening 70,000 compounds, he found one called TCA1 that was able to inhibit mycobacterial biofilms. When the researchers tested the compound in a biosafety level 3-certified laboratory, TCA1 was very active against TB, killing both replicating and nonreplicating TB bacteria. By itself, TCA1 killed more than 99.9 percent of actively replicating TB bacteria in three weeks; in combination with isoniazid and rifampin, the compound killed 100 percent in that time period. TCA1 was very effective against drug-resistant TB, removing all signs of one strain within a week when combined with isoniazid. When tested against a highly fatal “super-bug” strain from South Africa, which resists all conventional TB drugs, the new compound killed more than 99.999 percent in three weeks.
TCA1 also worked well against nonreplicating TB. Tests with mice showed TCA1’s effectiveness and suggested that combining TCA1 and isoniazid could be a more powerful treatment than the present anti-TB drugs. The compound showed no sign of toxicity or adverse side effects in cell culture and experiments with mice and no tendency to create drug resistance. Experiments and analyses to investigate how the new compound kills TB bacteria so efficiently indicated that the compound targets two enzymes in TB bacterium: one that supports TB replication and another TB dormancy and persistence.
With funding from the Global Alliance for TB Drug Development, Wang and colleagues are working to find improved variants of TCA1. If the preclinical tests are successful, the researchers will need a pharmaceutical partner to sponsor clinical trials in TB patients.
The full report, “Identification of a Small Molecule with Activity Against Drug-Resistant and Persistent Tuberculosis,” was published online the journal Proceedings of the National Academy of Sciences (2013; doi:10.1073/pnas.1309171110).