Sulphur dioxide, pretty notorious as a gaseous pollutant, may potentially have a role to play in tackling tuberculosis (TB), according to a recent paper by researchers at the Indian Institute of Science Education and Research (IISER), Pune. Their findings, potentially, open the door to the development of various sources of sulphur dioxide in the treatment of the infectious disease that affects millions globally every year.
Research into novel approaches to treat TB is driven by the need to tackle multi-drug-resistant strains of Mycobacterium tuberculosis (Mtb), the pathogenic bacterial species that causes the disease. What researchers also point out is that no new antibiotic has been approved for human use in more than four decades, despite the identification of molecular targets based on genomic and bioinformatic information relevant to Mtb.
Inspired by the ongoing clinical trials on the use of nitrogen oxide to combat the disease, the team from IISER’s chemistry department began looking at sulphur dioxide as a potential candidate for the job, a first-of its-kind effort.
?Nitrogen oxide, as is known, has been characterised as a pollutant and so is sulphur dioxide. So our hypothesis was, if we were able to make compounds that could generate sulphur dioxide, we would be able to target bacteria such as Mtb,? says Harinath Chakrapani, assistant professor at the chemistry department of IISER, Pune, and a co-author of the research paper that was published in the Journal of Medicinal Chemistry in January. The paper’s lead author Satish Malwal is a doctoral student at IISER, Pune, and the team comprised researchers from the department of pharmacy at Birla Institute of Technology and Science, Pilani, and the School of Biological Science at the National Institute of Science Education and Research, Bhubaneshwar.
The largest sources of sulphur dioxide emissions are fossil fuel combustion at power plants (73%) and other industrial facilities (20%), according to the US Environmental Protection Agency.
Though it was the first time anybody was looking at a reactive species of sulphur dioxide in treating tuberculosis, the gas is commonly used both as an antibiotic and an antioxidant. For centuries, it has been used as a preservative in wine-making because of its properties as an antioxidant. While it is well tolerated in humans, the key challenge, as the paper notes, was to control the delivery of sulphur dioxide to tap its therapeutic potential and possibly avoid undesirable side effects.
Chakrapani’s team at IISER studies ‘reactive species’ such as reactive oxygen species and reactive nitrogen species ? molecules that are generated in a controlled manner during immune responses to combat pathogens. By studying the effect these reactive species exert inside cells, the researchers aim to exploit the difference between a human cell’s response to a reactive species and to a bacterial cell for potential therapeutic applications.
?Logically, we thought if we can generate some reactive species in a controlled manner inside the bacterium perhaps we could kill this bacterium,? says Chakrapani. ?First, we wanted to show proof of concept because so far there are no organic compounds that have been designed and used to generate sulphur dioxide.?
Put simply, the researchers studied organic compounds that are activated by thiol ? the sulphur-bearing compounds naturally present in all living organisms ? to release sulphur dioxide, which eventually kills the bacterium. While sulphur dioxide will not be used directly as a ‘drug’ for tuberculosis, what the IISER research has shown is that a class of molecules, called 2,4-dinitrophenylsulfonamides, release sulphur dioxide in the presence of these thiols.
The team found that the anti-mycobacterial activity appeared to depend on the rate at which sulphur dioxide was generated from the compound. So, compounds that generate the gas faster were actually better in inhibiting Mtb growth.
?In a sense the molecules act as ‘pro-drugs’, which liberate the drug. This is nice and innovative work, and a very good proof of concept,? says Uday Maitra, professor, Department of Organic Chemistry at the Indian Institute of Science in Bangalore. ?Naturally, a lot of studies will have to be undertaken before one can use this principle to develop a drug.?
To build on their research, Chakrapani?s team is currently looking at detailed toxicological studies to find out how toxic the sulphur dioxide ‘prodrug’ can be to human cells. They will also have to identify the mechanisms and whether the compound targets some specific proteins or DNA or whether it merely a broad reactivity.
?Specifically we need to find out what are the targets in Mtb. That’s the kind of study that would help us to go forward,? says Chakrapani, whose group at IISER is also currently working on reactive oxygen species generators and hopes to publish a research paper by the end of the year. A third area of interest is the application of reactive nitrogen species specifically for tumor hypoxia, a condition where tumor cells develop low oxygen regions. ?We are looking to target hypoxia. It’s a pretty tough problem to work on, but we have just started working on it,? he says.
Statfacts
On brink of breakthrough
* Study involved organic compounds that release sulphur dioxide which kill Mycobacterium tuberculosis
* Compounds that generate sulphur dioxide faster were found to be better in inhibiting Mycobacterium tuberculosis (Mtb) growth
* New approaches to treat tuberculosis are driven by the need to tackle multi drug-resistant strains of Mtb
* Anti-mycobacterial activity appeared to depend on the rate at which sulphur dioxide was generated from the compound
* Team looking at detailed toxicological studies to find out how toxic the sulphur dioxide ?prodrug? can be to human cells
* The IISER, Pune, research is a sort of proof-of-concept, which would require further, extensive studies