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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).
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