As expected, TCA1 also showed potent effects against non-replicating TB. Tests in mice confirmed TCA1's effectiveness and suggested that the combination of TCA1 and isoniazid could be more powerful than existing drug regimens. TCA1 showed no sign of toxicity or adverse side effects in cell culture and mouse experiments, and also showed almost no tendency to induce drug resistance in TB.
A Complex Mechanism
Working with the laboratories of Gurdyal S. Besra and Klaus Ftterer at the University of Birmingham, UK, Katarina Mikusova at Comenius University in Slovakia, and Kai Johnson at Ecole Polytechnique Fdrale de Lausanne (EPFL) in Switzerland, the team next did structural and biochemical analyses to determine how the new compound kills Mtb so efficiently.
The researchers found it works in an apparently unique way, largely by targeting two Mtb enzymes, one supporting TB replication and the other TB dormancy and persistence. "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," Wang said.
Now funded by the Global Alliance for TB Drug Development, Wang and his colleagues are working to devise improved variants of TCA1. "We already have analogs of TCA1 that are more potent and look very promising as TB drug candidates," said Wang.
Assuming that preclinical tests are completed successfull
|Contact: Mika Ono|
Scripps Research Institute