TUBERCULOSIS is still one of the world鈥檚 biggest killers. No new drug has
been developed against TB for 30 years, and the disease is becoming increasingly
resistant to existing antibiotics, especially in the industrialised world. But
Canadian researchers told the ICAAC meeting about a chink in TB鈥檚 armour. They
have found a way to sabotage a key part of the bacterium鈥檚 biochemical
machinery.
Along with researchers at the University of British Columbia, a team led by
Barbara Waters and Julian Davies at TerraGen Discovery in Vancouver has
identified chemicals that inhibit key bacterial enzymes called protein kinases.
Once thought to be the preserve of plants and animals, protein kinases have
since turned up in bacteria. They are usually involved in transmitting signals
within cells. No one yet knows exactly what the 11 different kinases in the TB
bacterium do, but they may be important in the disease process.
Waters and Davies developed a 鈥渟creen鈥� that uses a distant relative of the TB
bacterium called Streptomyces to pick out drugs that inhibit kinases.
Streptomyces is a benign soil bacterium which goes through a stage
called sporulation, when it prepares to become dormant. Protein kinases control
sporulation, so it is an ideal testing ground for potential kinase
inhibitors.
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The Canadian team tested a number of compounds on Streptomyces,
including known kinase inhibitors, and identified several that stopped
sporulation. When they tested these compounds on the TB bacterium, they found
that six of them stopped bacterial growth in its tracks.
The interesting thing about these compounds, says Waters, is that they are
chemically very different from one another, providing wide scope for drug
development. What you don鈥檛 want, however, is these drugs interfering with human
protein kinases. Although this is a worry, Waters says you can probably make
inhibitors specific enough to inhibit just one type of enzyme. Other research
teams are developing a group of inhibitors called tryphostins to target a
protein kinase in human leukaemic cells, she adds.
Given the spectre of drug-resistant TB, the prospect of a new range of drugs
is encouraging. Waters hopes the Streptomyces screen will continue to
be useful. 鈥淲e think it has the potential to uncover new bioactive compounds,鈥�
she says.
