Resistance evolution in the presence of combination antibiotic therapy

Gwen Knight (primary)
London School of Hygiene and Tropical Medicine
Prof. Tim McHugh (secondary)
UCL Centre for Clinical Microbiology


Antimicrobial resistance (AMR) is a major global public health issue [1]. Antibiotic combination therapy is often used to prevent the spread of antibiotic resistance [2]. This presents a complex selection landscape for bacteria, with an interplay between mutation rates, fitness effects and epistasis determining the profile of the antibiotic resistant bacteria ultimately selected. This project will combine mathematical modelling with experimental analysis to explore resistance evolution within a pathogen group of importance in man and animals: the mycobacteria. The results will inform our understanding of the importance of heterogeneity in bacterial evolution but will also, ultimately, inform combination therapy design.


[1] Jim O’Neill Report:
[2] Kerantzas CA, Jacobs Jr. WR, Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application (2017). mBio vol. 8 no. 2 e01586-16
[3] Stagg, H. R., Lipman, M. C., McHugh, T. D., Jenkins, H. E. Isoniazid-resistant tuberculosis: a cause for concern? (2017) IJTLD. Vol 21, no 2, 129-139(11)
[4] Knight GM, Colijn C, Shrestha S, Fofana M, Cobelens F, White RG, Dowdy DW, Cohen T. (2015). The distribution of fitness costs of resistance-conferring mutations is a key determinant for the future burden of drug-resistant tuberculosis: a model-based analysis. CID. 61 Suppl.3
[5] da Foncesca JD, Knight GM, McHugh TD. (2015). The complex evolution of antibiotic resistance in Mycobacterium tuberculosis. International Journal of Infectious Diseases. 32:94-100

Genes, development and STEM* approaches to biology
Area of Biology
Techniques & Approaches
Mathematics / StatisticsMolecular BiologySimulation / Modelling