Mutagenesis and DNA repair in persistent cells at The University of Manchester on FindAPhD.com

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Dr Rok Krasovec, Prof Andrew McBain, Dr Katharina Edkins Applications accepted all year round Self-Funded PhD Students Only

Manchester United Kingdom Biophysics Evolution Genetics Microbiology

About the Project

Antimicrobial resistance is a global health problem, and we need new approaches to mitigate it. When a microbial community is treated with a lethal concentration of an antibiotic, the surviving cells are either genetically resistant or antibiotic tolerant. A subpopulation of tolerant cells called persisters are a major cause of chronic infections. Recent findings point to a general “low energy” mechanism of persister formation (Manuse et al. 2021). After the removal of the antibiotic, persisters can start to divide and eventually produce a lineage. What is the probability for persister’s descendants to acquire a genetic mutation?

In this interdisciplinary project, the candidate will quantify mutations in individual cells descendant from a persister and determine the effects of the genotype, stochastic heterogeneity and microenvironments on the mutation dynamics. The candidate will also test how different types of antibiotics, their combinations and treatment regimes affect the fate of persisters and their lineages.

We shall accomplish this with microbiology, single-molecule, and single-cell approaches, which includes a polydimethylsiloxane microfluidics and super-resolution microscopy. The project will be an iteration between live cell microscopy of persisters confined to microfluidic chambers, genetic engineering and environmental manipulations.

Studying persisters and their lineage will increase our fundamental understanding of molecular processes involved in antibiotic tolerance and genetic resistance, which enable us to better predict and more sustainably combat the antimicrobial resistance.

References

Manuse S, Shan Y, Canas-Duarte SJ, Bakshi S, Sun W-S, Mori H et al (2021). Bacterial persisters are a stochastically formed subpopulation of low-energy cells. PLoS Biol 19: e3001194.
Pu, Y. et al. ATP-Dependent Dynamic Protein Aggregation Regulates Bacterial Dormancy Depth Critical for Antibiotic Tolerance. Molecular Cell 73, 143-156.e144, doi:10.1016/j.molcel.2018.10.022 (2019).
Barrett, T. C., Mok, W. W. K., Murawski, A. M. & Brynildsen, M. P. Enhanced antibiotic resistance development from fluoroquinolone persisters after a single exposure to antibiotic. Nat. Commun. 10, 1177-1177, doi:10.1038/s41467-019-09058-4 (2019).
Cirz, R. T. et al. Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS biology 3, e176, doi:10.1371/journal.pbio.0030176 (2005).
Krašovec, R. et al. Spontaneous mutation rate is a plastic trait associated with population density across domains of life. PLoS Biol. 15, e2002731, doi:10.1371/journal.pbio.2002731 (2017).