Li Anqi, He Siyuan, Jia Yaping, Fan Junsheng, Liu Shicong, Wang Xinghai, Zhang Zhemin, Chu Haiqing
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
School of Medicine, Tongji University, Shanghai, China.
Clin Exp Pharmacol Physiol. 2025 Apr;52(4):e70024. doi: 10.1111/1440-1681.70024.
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.
脓肿分枝杆菌是一种多重耐药病原体，带来了重大的治疗挑战。本研究评估了亮氨酰 - tRNA合成酶抑制剂MRX - 6038的口服前药MRX - 5对脓肿分枝杆菌的体内外疗效。在35°C的Middlebrook 7H9肉汤中使用液相色谱 - 串联质谱法对MRX - 5进行稳定性测试。随后，测定了MRX - 5对两株参考菌株和17株脓肿分枝杆菌临床分离株的最低抑菌浓度。在体内实验中，首先评估了MRX - 5的药代动力学特性，然后在脓肿分枝杆菌肺部感染的中性粒细胞减少的BALB / c小鼠模型中进行疗效测试。值得注意的是，MRX - 5在液体肉汤中72小时内完全转化为MRX - 6038，并且在体外MRX - 5的效力低于MRX - 6038。在体内，MRX - 5有效地转化为MRX - 6038，口服生物利用度达到83.95%，并在肺部有显著分布。在肺部脓肿分枝杆菌感染的小鼠模型中，MRX - 5有效降低了细菌载量，并且表现出与利奈唑胺相当的抗菌活性。总之，MRX - 5在肺部具有良好的分布，并且对脓肿分枝杆菌具有体内疗效，使其成为口服治疗脓肿分枝杆菌感染的有前景的候选药物。
