Abstract
The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs.
Highlights
Tuberculosis, which is caused by the bacterial pathogen Mycobacterium tuberculosis (M.tuberculosis), is a leading cause of mortality among infectious diseases
The effective treatment of multi-drug resistant (MDR)-TB necessitates the long-term use of second-line drug combinations, an unfortunate consequence of which is the emergence of extensively drug resistant tuberculosis (XDR-TB) – M.tuberculosis strains that are resistant to isoniazid plus rifampin, as well as key second-line drugs, such as ciprofloxacin and moxifloxacin
It is interesting to note that both nicotinamide adenine dinucleotide (NAD) and S-adenosyl methionine (SAM) include adenine as a common molecular fragment
Summary
Tuberculosis, which is caused by the bacterial pathogen Mycobacterium tuberculosis (M.tuberculosis), is a leading cause of mortality among infectious diseases It has been estimated by the World Health Organization (WHO) that almost one-third of the world’s population, around 2 billion people, is infected with the disease [1]. More than 8 million people develop an active form of the disease, which subsequently claims the lives of nearly 2 million This translates to over 4,900 deaths per day, and more than 95% of these are in developing countries [2]. The effective treatment of MDR-TB necessitates the long-term use of second-line drug combinations, an unfortunate consequence of which is the emergence of extensively drug resistant tuberculosis (XDR-TB) – M.tuberculosis strains that are resistant to isoniazid plus rifampin, as well as key second-line drugs, such as ciprofloxacin and moxifloxacin. The rise of XDR-TB around the world, including in industrialized nations, imposes a great threat on human health, emphasizing the need to identify new anti-tubercular agents as an urgent priority [4]
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