Marriott, AAN; (2016) The influence of growth conditions on the susceptibility of Mycobacterium tuberculosis to antibiotics. Doctoral thesis , UCL (University College London).

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Abstract

Mycobacterium tuberculosis is the causative agent of tuberculosis disease which is a global health emergency. Lengthy treatment is required due to the intrinsic resistance of M. tuberculosis to most classes of antibiotics and continued survival of drug tolerant persisting populations. This tolerance and persistence may be because of pre-existing populations of bacteria recalcitrant to treatment through phenotypic mechanisms such as slow growth or nonreplicating persistence; or through genotypic alterations resulting in resistance phenotypes. In order to improve treatment, effective in vitro modelling of these populations and factors affecting efficacy is essential. Cell density, growth rate and growth phase were all found to affect the efficacy of isoniazid and rifampicin in this study. M. tuberculosis grown at a high cell density was shown to be less susceptible to antibiotic exposure, this was particularly true for rifampicin. Growth phase was also considered, in the host, a bacterium is likely to encounter nutrient depletion and enter stationary and non-replicating phases. Isoniazid and rifampicin were both less effective the longer M. tuberculosis was in culture. This work demonstrated the need for consideration of multiple factors when designing and modelling treatment of tuberculosis. Using continuous culture M. tuberculosis was grown at a fast (23.1 hours) and slow (69.3) doubling times, with and without isoniazid exposure aiming to elucidate the different responses these populations may have to antibiotic. Genotypic analyses showed that slow growing bacilli developed resistance to isoniazid through mutations specifically in katG codon Ser315 which are present in approximately 50–90% of all isoniazid-resistant clinical isolates. The fast growing bacilli persisted as a mixed population with katG mutations distributed throughout the gene. Phenotypic differences were detected between the populations at the two growth rates including expression of efflux mechanisms and the involvement of antisense RNA/small RNA in the regulation of a drug-tolerant phenotype.

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