Epistasis and Antimicrobial Drug Resistance in Tuberculosis

In this PhD, you will undertake research into the phenomenon known as epistasis in Mycobacterium tuberculosis.   Epistasis refers to the effect that genetic background can have on the fitness of a mutation.  In the context of drug resistance, interactions between resistance mutations can have important implications for the evolution of multi-drug resistance.  The focus of this PhD will be to characterise epistasis for key first and second line antitubercular drugs in the context of drug resistance evolution and clinical management of tuberculosis (TB).  The PhD will involve a number of research elements including molecular biology and development of fluorescent biological probes, whole genome sequencing, high content imaging, single-cell microfluidics, pharmacology and bioinformatics.  Extensive training will be afforded in all of these areas including with industry and collaborators (e.g. South Africa, Vietnam) as well as external institutions (e.g. Sanger Centre)

Where does the project lie on the Translational Pathway?

T1 – Basic Research

Expected Outputs

  • The project will develop outputs that will give insight into clinical and epidemiological observations of drug resistance and information that can be used to help with clinical management of drug resistance
  • The candidate will develop a strong skill set (output = PhD) and develop a network of academic and industrial collaborators

 

  • The project will produce high quality REF returnable 3*/4* publications.

 

  • The project will develop data for on-ward funding/research programmes

 

  • Presentation at international conferences

 

Training Opportunities

Training  will be provided in :

 

  • HG3 Microbiology
  • Molecular biology – development of fluorescent reporter strains, whole genome sequencing
  • Set up of Microfluidics platforms for single cell measurements
  • Confocal microscopy imaging
  • Bioinformatics -molecular evolution, comparative genomics, population genomics);
  • statistics;

 

The student will work with collaborators from a number of collaborators including: Evotech Pharmaceuticals, Cape Town University, Wellcome Trust Sanger Institute and Vietnam TB Centre, Hanoi.  Training as a “Bridge” scientist through interaction with the interdisciplinary Centre for Drug and Diagnostic Discovery

 

Skills Required

The student should be comfortable working in microbiology, imaging and bioinformatics/computational biology, and have an interest in infectious disease epidemiology and clinical microbiology/TB.

Key Publications associated with this project

Wong, A.   Epistasis and the Evolution of Antimicrobial Resistance

Front Microbiol. 2017; 8: 246.

 

Dookie, Navisha; Rambaran, Santhuri; Padayatchi, Nesri; et al. Evolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care  JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY   Volume: 73   Issue: 5   Pages: 1138-1151  

Podnecky, Nicole L.Fredheim, Elizabeth G. A.Kloos, Julia; et al. Conserved collateral antibiotic susceptibility networks in diverse clinical strains of Escherichia coli. NATURE COMMUNICATIONS   Volume: 9     Article Number: 3673   Published: SEP 10 2018

 

Donnellan S, Aljayyoussi G, Moyo E, Ardrey A, Martinez-Rodriguez C, Ward SA, Biagini GA. Intracellular pharmacodynamic modelling (PDi) is predictive of the clinical activity of fluoroquinolones against Tuberculosis. Antimicrob Agents Chemother. 2019 Oct 14. pii: AAC.00989-19. doi: 10.1128/AAC.00989-19

 

LSTM Themes and Topics – Key Words

Resistance research and management

The call for applications for the 2020-21 round of studentships is now OPEN. Deadline for receipt of complete application 23:59 13th February 2020

Further information on the programme and application process can be found here