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(BBSRC DTP) Mutagenesis and DNA repair in persistent cells


   Faculty of Biology, Medicine and Health

  , ,  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

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 

Eligibility 

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.  

Before you Apply 

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.  

How To Apply 

To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/  

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team   

Equality, Diversity and Inclusion  

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/  


Funding Notes

Studentship funding is for 4 years. This scheme is open to both the UK and international applicants. We are only able to offer a limited number of studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

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).

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