Every year, around the world, more than 9 million people die of tuberculosis. Mycobacterium tuberculosis, the causative bacteria, depend on iron as their single most important micronutrient. Is iron the Achilles heel? Can we attack the bacteria that cause TB by depleting iron?
So Zeeshan Fatima and Saif Hameed from the Amity University, Gurugram collaborated with researchers from the AIIMS, New Delhi to test how iron deprivation affects Mycobacterium tuberculosis.
To create an iron deficient environment they used a chelator that binds to iron. Then they subjected TB bacteria grown under iron-depletion to four well-known antitubercular drugs.
The team found that, in the iron-deficient environment, the bacteria succumbed to anti-TB drugs more easily. The drugs proved more lethal and the minimum concentration needed to inhibit the growth of the bacteria was reduced.
The bacteria’s morphology, a scanning electron microscope revealed, changed. Was the cell wall affected? To check, the researchers used DNA labelling dyes. These dyes enter cells and stain the nucleic acid only if the cell wall is disrupted. Both dyes showed up in TB bacteria exposed to an iron-deficient environment. So iron deficiency, say the researchers, does indeed disrupt the bacterial cell wall.
They also found that iron deficiency leads to the downregulation of many genes. Besides the iron regulatory gene, β-glucosidase enzyme and lipid biosynthesis genes were also found to be less active. The downregulation of these genes changes the protective lipid layers of the bacteria.
Bacterial biofilm formation is a major forerunner in the pathogenesis of the disease. The team discovered that the activity of the genes responsible for biofilm formation was also reduced under iron depletion. Iron-deprived bacteria, report the researchers, show less aggregation and they reduce in mass.
Carbohydrate synthesis as well as bacterial persistence and virulence depend on the glyoxylate pathway and any variations in the cycle kill the bacteria. So Zeeshan and her team examined the effect of iron deficiency on two critical enzymes of the glyoxylate pathway. Both enzymes, they found, become inactive under iron deficiency. This directly affects the survivability of the bacteria.
The team also examined the bacteria’s ability to cause disease by infecting Caenorhabditis elegans, a popular animal model for human diseases. And they discovered that TB bacteria with iron deficiency couldn’t survive to cause the disease as they did in the control.
Iron-citrate in blood is the iron source for the Mycobacterium species. So limiting access to this source may prove an additional way to deal with tuberculosis. What strategy should we use to inhibit the TB bacteria’s access to this resource without harming humans who harbour the disease?
In science, often an answer opens up new questions.
3 Biotech, 9 (4): 122 (2019); DOI: 10.1007/s13205-019-1645-4
Dhanashree, CFTRI, Mysuru