Abstract
Over 1.6 million people died from tuberculosis (TB) in 2021. While drug-susceptible cases can be treated with a combination of antibiotics that achieve ~85% cure rates, patient non-adherence, suboptimal drug penetration, and improper treatment can result in the emergence of drug-resistant isolates. While the development of new anti-TB drugs is required, the process is time-consuming and costly. This highlights the need for new antibiotic regimens that can improve treatment success and prevent the spread of resistance. While drug resistance is associated with treatment failure, there is mounting evidence to suggest that it can exploited to improve treatment outcomes. Collateral sensitivity is the phenomenon where the development of drug resistance is associated with an increased sensitivity to another unrelated drug. While the current research into this topic focuses on drug-resistant forms of cancer, there has been promise from clinical studies that saw success in targeting these acquired vulnerabilities. Understanding the interactions between drug-resistant isolates and their increased antibiotic sensitivities would allow for the design of treatment regimens which can prevent the emergence of drug resistance or specifically target drug-resistant cells. By using a collection of mono-drug resistant M. tuberculosis isolates, this study aimed to investigate changes in antibiotic susceptibility to identify interactions which can be used to design improved treatment regimens. By using drug susceptibility profiling, genomics and evolutionary studies, this thesis provides evidence that drug-resistant M. tuberculosis experiences collateral sensitivity during sequential antibiotic treatment. As a proof-of-concept, this thesis shows that collateral sensitivities can be exploited to slow or prevent the emergence of drug resistance. Furthermore, this thesis provides evidence that supports the previous observation that some antibiotics may initiate the production of reactive oxygen species, improving antibiotic-mediated cell damage. Additionally, this large-scale study design included a collection of antibiotics which are currently used, those in clinical development, as well as antibiotics with efficacy against M. tuberculosis, allowing for the potential to uncover novel cross-resistance mechanisms. Consistently, this thesis adds to the collection of antibiotics which are exported by the MmpL5/MmpS5 efflux pump and provides evidence that the similarity to the pump’s natural substrate mediates drug export. Combined, the identification of collateral sensitivities and novel cross-resistance mechanisms
in M. tuberculosis provides important information which can be used to design better treatment regimens to specifically target drug-resistant cells, avoid known cross-resistance mechanisms, and to reduce the emergence of antibiotic resistance.