<scp>LeuRS</scp>‐Targeting Prodrug, <scp>MRX</scp>‐5, Expresses Anti‐<scp><i>Mycobacterium abscessus</i></scp> Activity

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.