Researchers at the University of California, San Diego and the University of Leeds, U.K. have linked hundreds of FDA approved drugs to more than 1,000 proteins in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB).
The study, which opens new avenues to repurpose these drugs to treat TB, will be published in the November 4th issue of the open-access journal PLoS Computational Biology.
“Tuberculosis is currently one the most widely spread infectious diseases, with an estimated one-third of the world’s population infected and between one and two million people dying each year from the disease.
The continuing emergence of M. tuberculosis strains resistant to all existing, affordable drug treatments requires the development of novel, effective and inexpensive drugs,” said Philip Bourne, PhD, professor of pharmacology at UCSD’s Skaggs School of Pharmacy and Pharmaceutical Sciences.
The identification of new M. tuberculosis protein targets that can be perturbed by a variety of existing drugs prescribed for other purposes (drug repurposing) may open avenues to discover new therapeutics to treat drug resistant tuberculosis in an inexpensive and safe manner, Bourne added
Sarah Kinnings, from the University of Leeds, and a team at UC San Diego, led by Bourne – who is also associate director of the RCSB Protein Data Bank – and research scientist Lei Xie, PhD, have used a novel computational strategy to investigate whether or not existing drugs may be able to bind to any of the approximately 40 percent of proteins in the M. tuberculosis proteome with decipherable three-dimensional structures.
The researchers not only discovered that approximately one-third of the drugs examined may have the potential to be repurposed to treat tuberculosis, but also that many currently unexploited M. tuberculosis proteins could serve as novel anti-tubercular targets.
This finding led the investigators to construct a complex network of drug-target interactions, the TB-drugome, which is freely available for all scientists to use.
“While this new computational, high-throughput process of drug discovery is promising, only experiment can validate the most promising drug-target combinations, and there will be many failures along the way,” said Xie.
Kinnings added that any drugs that are subsequently confirmed to bind to M. tuberculosis proteins may need to be modified to increase their ability to penetrate the bacterial cell membrane, reduce their required dosage, and improve other pharmacological properties. The screening of a large collection of analogs to known drugs will be the next step towards anti-tuberculosis drug discovery.
Source: PLoS Computational Biology