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Mutation rate and antimicrobial resistance in Mycobacterium tuberculosis


   Faculty of Biology, Medicine and Health


About the Project

Mycobacterium tuberculosis, an agent of tuberculosis (TB), evolves resistance to first-line anti-TB drugs via de novo mutations. Such a mutation-based resistance in M. tuberculosis is a massive global health problem and we need new approaches to tackle it.

This interdisciplinary project stems from our discovery that bacterial pathogens at lower population densities have up to 23-fold higher chance of becoming resistant to multiple antibiotics, including an anti-TB drug rifampicin. We named this fundamental insight of high mutation rates at low cell-density, a density-associated mutation rate plasticity, or DAMP.

The candidate will study how environmental conditions such as population density, oxygen availability and various drugs affect the mutation rate of M. tuberculosis. Mutation rates will be quantified with high-throughput fluctuation assays and with an advanced microscopy that will include a combination of polydimethylsiloxane microfluidics and a super-resolution microscopy.

Studying mutation rates in M. tuberculosis is crucial for developing new clinical approaches that will mitigate drug resistance and improve treatment of TB. Finding conditions where mutation-based resistance in M. tuberculosis is minimal could underpin the development of adjuvants that will give new life to first-line anti-TB drugs. 


References

- Krašovec, R. et al. Mutation rate plasticity in rifampicin resistance depends on Escherichia coli cell-cell interactions. Nat. Commun. 5, 3742, doi:10.1038/ncomms4742 (2014).
- Krašovec, R. et al. Measuring Microbial Mutation Rates with the Fluctuation Assay. JoVE, e60406, doi:doi:10.3791/60406 (2019).
- Fernández-Soto P, Casulli J, Solano-Castro D, Rodríguez-Fernández P, Jowitt TA, Travis MA et al (2021). Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis. Scientific Reports 11: 7667.

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