Most humans would like to shed their fatty exteriors, but tuberculosis (TB)-causing bacteria rely on theirs for survival. Scientists at the University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical School have now discovered a drug that cripples the TB bug by dissolving its protective fatty coating, a finding that could eventually be used to improve TB treatment in humans. The study has been posted online by Nature Chemical Biology.
TB is caused by infection with the bacterium Mycobacterium tuberculosis (Mtb) and is the second biggest cause of death worldwide, second only to HIV/AIDS. And with drug-resistant strains of Mtb on the rise, there is a critical need for more effective anti-TB agents.
"Mtb is a little ball of soap," says lead author David Alland, MD, a professor of medicine and Director of the Center for Emerging and Re-emerging Pathogens at New Jersey Medical School, describing the meshwork of long fatty acids that make up the bug's protective cell wall. There are a few anti-TB drugs that disrupt this coat, but so far no single drug has been able to kill the bacteria completely. So his group went in search of new and better drugs by using a simple and rapid approach. They screened for agents that trigger expression of a bacterial gene that gets turned on when cell wall synthesis is compromised.
They discovered a class of compound called thiophenes that killed the Mtb in culture without the emergence of drug resistance. And the combination of thiophene and the existing coat-busting drug isoniazid achieved 100% bacterial killing. Thiophenes worked by crippling an enzyme called Pks13 that hitches two long fatty acids together to create the bug's fatty coat. With additional information on the molecular structure of these drugs bound to Pks13, Alland hopes to discover ways to tweak the compounds to make them even more potent and less toxic.
The above story is based on materials provided by University of Medicine and Dentistry of New Jersey (UMDNJ). Note: Materials may be edited for content and length.
- Regina Wilson, Pradeep Kumar, Vijay Parashar, Catherine Vilchθze, Romain Veyron-Churlet, Joel S Freundlich, S Whitney Barnes, John R Walker, Michael J Szymonifka, Emily Marchiano, Shubhada Shenai, Roberto Colangeli, William R Jacobs, Matthew B Neiditch, Laurent Kremer, David Alland. Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nature Chemical Biology, 2013; DOI: 10.1038/nchembio.1277
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