Making common antibiotics powerful against tuberculosis

Beta-lactam antibiotics such as penicillin and amoxicillin are the most commonly used drugs against bacterial infections. However, beta-lactams remain completely ineffective in killing tuberculosis (TB) causing bacteria, Mycobacterium tuberculosis (Mtb). This is because Mtb inherently produce an enzyme called beta-lactamase, which breaks down beta-lactams and makes the drug ineffective against TB disease. One way to overcome this is by using the beta-lactams in combination with an inhibitor of beta-lactamase enzyme. Clavulanic acid is one such inhibitor, which when combined with a beta-lactam antibiotic (amoxicillin), commonly sold under the brand name Augmentin, effectively targets Mtb. However, the exact mechanism of how Augmentin kills Mtb and how bacteria can develop resistance against Augmentin was not known. We first examined how bacteria sense the presence of Augmentin. We found that Mtb produces sub-lethal amount of reactive oxygen species (ROS) upon seeing Augmentin. The ROS acts as an indicator of danger, to which Mtb needs to mount a defence response. This defence is through a protein called WhiB4, which senses the ROS signal and increased the production of beta-lactamase enzyme and antioxidants. Beta-lactamase breaks down the Beta-lactam part of Augmentin and antioxidants detoxify ROS produced upon drug exposure. Both beta-lactamase and antioxidant together contribute to resistance against Augmentin. Based on these findings we demonstrated that it is possible to kill drug-resistant Mtb by simply changing the levels of the regulator, WhiB4, and/or increasing the ROS levels inside the bacteria. The excessive ROS inside the bacteria will help in killing the drug-resistant TB bacteria.

Reference:
Mishra S., Shukla P., Bhaskar A., Anand K., Baloni P., Jha KR., Mohan A., Rajmani RS., Nagaraja V., Chandra N., and Singh A. (2017) Efficacy of β-lactam\β-lactamase inhibitor combination is linked to WhiB4 mediated changes in redox physiology of Mycobacterium tuberculosis. eLife. 6:e25624 doi: 10.755/ELIFE.25624.

Website: http://mcbl.iisc.ac.in/Amit-Singh

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