LeuRS‐Targeting Prodrug, MRX‐5, Expresses Anti‐Mycobacterium abscessus Activity

ABSTRACT Mycobacterium abscessus is a multi‐drug resistant pathogen presenting significant treatment challenges. This study evaluated MRX‐5, an oral prodrug of the leucyl‐tRNA synthetase inhibitor MRX‐6038, for its efficacy against M. abscessus both in vitro and in vivo. Stability testing of MRX‐5 was conducted using liquid chromatography–tandem mass spectrometry in Middlebrook 7H9 broth at 35°C. Following this, the minimum inhibitory concentrations of MRX‐5 were determined against two reference strains and 17 clinical isolates of M. abscessus . In the in vivo experiments, the pharmacokinetic properties of MRX‐5 were assessed first, followed by efficacy testing conducted in a neutropenic BALB/c mouse model of M. abscessus lung infection. Remarkably, the conversion of MRX‐5 to MRX‐6038 in liquid broth was complete within 72 h, and MRX‐5 demonstrated reduced potency compared to MRX‐6038 in vitro. In vivo, MRX‐5 was efficiently converted to MRX‐6038, achieving an oral bioavailability of 83.95% and significant lung distribution. In the mouse model of pulmonary M. abscessus infection, MRX‐5 effectively reduced bacterial load and exhibited antimicrobial activity comparable to that of linezolid. In conclusion, MRX‐5 exhibited favourable lung distribution and in vivo efficacy against M. abscessus , positioning it as a promising candidate for the oral treatment of M. abscessus infections.