Pretomanid is a bicyclic nitroimidazole and small molecule pro-drug that is active against actively replicating and hypoxic non-replicating Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). It is activated by deazaflavin-dependent nitroreductase. Other mono- and multidrug-resistant strains of M. tuberculosis exhibited comparable susceptibilities to Pretomanid, indicating no cross-resistance with current anti-TB drugs.
|Mechanism of Action||
Pretomanid has a complex mechanism of action, with differing aerobic and anaerobic activity. Aerobic activity includes cell wall inhibition via mycolic acid biosynthesis. Anaerobic activity has Pretomanid acting as a nitric oxide donor, resulting in respiratory poisoning through nitric oxide release. The nitric oxide possibly reacts with cytochromes to interfere with electron flow and ATP homeostasis under hypoxic conditions. Nitric oxide has multiple targets including as many as 29 mycobacterial enzymes (Manjunatha et al, 2009).
Understanding the interaction between Pretomanid and the target bacterial metabolome is important to contribute to the discovery of new TB candidates.
|Spectrum||Effective against Mycobacteria tuberculosis.|
Pretomanid was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates tested (MIC<1 ug/ml) (Lenaerts et al, 2005).
Pretomanid was also tested on M. tuberculosis growing as a biofilm/pellicle, a bacterial phenotype known to be more resistant to antibiotic treatment. Light levels from bioluminescently-labeled M. tuberculosis were used as a surrogate for bacterial viability. The organism growing as this phenotype was resistant to the majority of compounds tested, with MICs increasing from 20-fold to > 1000-fold.(Dalton et al, 2016). Pretomanid MIC value of Pretomanid against bacteria growing in a planktonic way was 0.011 mg/L and increased to >3.6 when it was compared to the biofilm phenotype (Dalton et al, 2016).
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