In a recent collaborative study, a team of researchers from Hungary, India, France and the USA has explored the potential of some new chemical compounds as therapeutic agents against tuberculosis (TB). Caused by the bacteria Mycobacterium tuberculosis, TB is a leading cause of death worldwide claiming over 1.7 million lives per year. Although medicines are available for successful treatment of the disease, some TB bacteria have developed resistance against most of these drugs, making it a challenge to tackle the disease.
Hence, scientists around the world are looking for novel approaches to counter drug-resistant tuberculosis. “The increasing number of drug-resistant TB cases provide a strong incentive to find new, effective antituberculosis agents, potentially avoiding bacterial drug-resistance,” remark the researchers of the current study, published in the journal PLoS ONE and supported by the Department of Science and Technology, Government of India, along with other international funding agencies.
The researchers of the current study have targeted the bacterial enzyme topoisomerase-I, essential for DNA repair in the bacteria. In previous research, they had studied the interaction of some chemical compounds developed by a company called Vichem Chemie Research Ltd. They used a computer-based technique called molecular docking to investigate the interaction between the compounds and the enzyme. In this study, the researchers have shortlisted seven promising topoisomerase inhibitors for a detailed investigation. The study finds that all the seven compounds completely inhibit the activity of the topoisomerase-I enzyme and four of them were able to inhibit the growth of the TB bacteria.
A successful therapeutic agent, apart from acting against the targeted chemical or organism, must also be non-toxic to our body. The researchers of the study confirmed the non-toxicity of the possible drug compounds by testing them on cells grown in the laboratory. “Although their antimycobacterial effects were promising, some of the Vichem compounds examined were toxic in at least one of the examined cell lines. Therefore, those cannot be considered as promising candidates for the treatment of TB,” comment the researchers on their findings.
Along with the various mechanisms in the TB bacteria that contribute to the development of resistance, some components in our cells are also responsible. A family of proteins, called the ATP-binding cassette (ABC) transporters, is involved in the regulation of absorption, distribution, and toxicity of drugs. They contribute to drug resistance by pumping out the drugs from our cells. The researchers studied the interaction of the Vichem compounds with these transporters and found that one compound fulfils all the necessary criteria to be used as a potential anti-TB agent.
“The compound VCC891909 showed efficient topoisomerase inhibition, Mycobacterium tuberculosis growth inhibitory effect, and no mammalian cell toxicity without a significant human ABC transporter interaction. Therefore, this compound may be an especially favourable candidate for antimycobacterial drug development”, say the researchers.
The study is one of the many attempts at tackling tuberculosis by a focused pre-screening system for the development of targeted drugs. Such compounds represent new possibilities for further anti-TB drug development, conclude the researchers.