Same class, different activity: Delamanid and pretomanid have comparable bactericidal activity but pretomanid potently inhibits Mycobacterium tuberculosis ribosomal rRNA synthesis

Abstract

BackgroundThe nitroimidazoles delamanid and pretomanid play an important role in contemporary tuberculosis treatment. It is unclear whether delamanid and pretomanid have meaningfully different activity since both reduce Mycobacterium tuberculosis colony forming units (CFU) similarly in animal models. The RS ratio is a pharmacodynamic marker of ongoing rRNA synthesis that has been associated with treatment-shortening (i.e., sterilizing) activity. MethodsUsing Mycobacterium tuberculosis Erdman, we conducted dose-ranging studies in aerobic axenic culture and in the conventional BALB/c mouse high-dose aerosol infection model to compare bactericidal and RS ratio activity of delamanid and pretomanid. ResultsIn vitro concentration-response curves showed that delamanid and pretomanid had similar RS ratio effect at maximal concentration but pretomanid was more potent, achieving 90% of the maximal effect (RS-EC90) at a lower concentration (390 ng/mL) than delamanid (810 ng/mL). In mice, delamanid and pretomanid had similar effects on CFU. Human-equivalent doses of delamanid (6 mg/kg) and pretomanid (50 mg/kg) resulted in plasma Cmax concentrations well below (210 ng/mL) and well above (7,825 ng/mL) the RS-EC90, respectively. Delamanid displayed no discernable RS ratio response, even at 16-times the human-equivalent dose. Higher pretomanid doses resulted in significantly greater RS ratio effects. ConclusionsWe found that delamanid and pretomanid have similar bactericidal activity but pretomanid has superior RS ratio activity. Meaningful differences between drugs within the same class were not captured by conventional CFU-based pharmacodynamics, supporting the value of measuring orthogonal drug effects such as the RS ratio. LAY SUMMARYAntibiotics in the nitroimidazole class are used in treatment of drug-resistant tuberculosis. There are two approved nitroimidazole antibiotics: delamanid and pretomanid. For decades, it has been unclear whether delamanid and pretomanid are interchangeable or whether they affect the bacterium M. tuberculosis differently. Most studies of the effect of antibiotics count the number of bacterial colonies that form on a culture plate. "Colony forming units" tell us about change in bacterial burden but does not give information about bacterial health. A new way of thinking about antibiotic effect is the RS ratio. The RS ratio is a test that measures how much ribosomal RNA synthesis is ongoing. Ribosomal RNA synthesis is a "vital sign" of bacterial health and activity. The key finding of this study is that although the two nitroimdazole antibiotics look the same in terms of their effect on bacterial burden, they have different effects on bacterial health. This information deepens understanding of differences between two clinically important antibiotics. It also shows that antibiotics testing should consider not only bacterial burden but also new tests of bacterial health.