In vitro resistance to TMC207/R207910

Wednesday, December 30th, 2009 by hinrich

Structure of TMC207/R207910

In the article "Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor" Huitric et al. looked at almost 100 different bacterial mutants that the authors identified from clinical isolates. They tried to establish how quickly M. tuberculosis can develop mutations in vitro that will confer resistance to the new investigational drug TMC207/R207910. Furthermore, Huitric et al. were interested in studying the mutants in more detail to learn about the mechanisms by which the bacterium can escape the bactericidal effect of TMC207/R207910.

When looking at the level of resistance, the authors determined a 4- to 128-fold increase in MIC (Minimum Inhibitory Concentration). Increasing the concentration of TMC207/R207910 resulted in a decrease of the rate at which high-level resistence occurred. How does this in vitro result translate to the clinical context? If the therapeutic dose in patients could be equal to or higher than the concentration at which such mutations do not occur while still avoiding toxicity, the positive effects of TMC207/R207910 might be even higher as clinical resistance would be less frequent.

Huitric et al. also studied the sequence of one or more of the genes that encode the bacterial ATP synthase in approximately half of the mutants. The authors identified mutations that would result in five different amino acid substitutions in the atpE gene. This gene had previously been identified and linked to the novel mechanism of action of TMC207/R207910. However, for 38 of the mutants no further mutations in the ATP synthase related genes were identified. This suggests that Mycobacterium tuberculosis has different mechanisms by which the bacterium can escape the effects of TMC207/R207910.

A review of the mechanism of action of TMC207/R207910 can be found in this Science Enhanced Perspectives article (free access). The article by Huitric et al. has just been published in Antimicrobial Agents and Chemotherapy. Please have a look here for further information.

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