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A Novel Leucyl-tRNA Synthetase Inhibitor, MRX-6038, Expresses Anti-Mycobacterium abscessus Activity In Vitro and In Vivo. 2022

Wenye Wu, and Siyuan He, and Anqi Li, and Qi Guo, and Zhili Tan, and Shicong Liu, and Xinghai Wang, and Zhemin Zhang, and Bing Li, and Haiqing Chu
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

Therapeutic options for Mycobacterium abscessus infections are extremely limited, and new drugs are needed. The anti-M. abscessus activity of MRX-6038, a new leucyl-tRNA synthetase inhibitor, was evaluated in vitro and in vivo. Antimicrobial susceptibility testing was performed on 12 nontuberculosis mycobacteria (NTM) reference strains and 227 clinical NTM isolates. A minimum bactericidal concentration assay was conducted to distinguish the bactericidal versus bacteriostatic activity of MRX-6038. The synergy between MRX-6038 and 12 clinically important antibiotics was determined using a checkerboard assay. The activity of MRX-6038 against M. abscessus residing inside macrophages was also evaluated. Finally, the potency of MRX-6038 in vivo was determined in a neutropenic mouse model that mimicked a pulmonary M. abscessus infection. MRX-6038 exhibited high anti-M. abscessus activity against extracellular M. abscessus in culture, with a MIC50 of 0.063 mg/L and a MIC90 of 0.125 mg/L. Fifty percent of the activity was bactericidal, and fifty percent was bacteriostatic. A synergy between MRX-6038 and clarithromycin or azithromycin was found in 25% of strains. No antagonism was evident between MRX-6038 and 12 antibiotics commonly used to treat NTM infections. MRX-6038 also exhibited activity against intracellular NTM, which caused a significant reduction in the bacterial load in the lungs of M. abscessus-infected neutropenic mice. In conclusion, MRX-6038 was active against M. abscessus in vitro and in vivo, and it represents a potential candidate for incorporation into strategies by which M. abscessus infections are treated.

UI MeSH Term Description Entries
D007935 Leucine-tRNA Ligase An enzyme that activates leucine with its specific transfer RNA. EC 6.1.1.4. Leucyl T RNA Synthetase,Leu-tRNA Ligase,Leucine-tRNA Synthetase,Leu tRNA Ligase,Leucine tRNA Ligase,Leucine tRNA Synthetase,Ligase, Leu-tRNA,Ligase, Leucine-tRNA,Synthetase, Leucine-tRNA
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D009165 Mycobacterium Infections, Nontuberculous Infections with nontuberculous mycobacteria (atypical mycobacteria): M. kansasii, M. marinum, M. scrofulaceum, M. flavescens, M. gordonae, M. obuense, M. gilvum, M. duvali, M. szulgai, M. intracellulare (see MYCOBACTERIUM AVIUM COMPLEX;), M. xenopi (littorale), M. ulcerans, M. buruli, M. terrae, M. fortuitum (minetti, giae), M. chelonae, M. leprae. Mycobacterium Infections, Atypical,Atypical Mycobacterial Infection, Disseminated,Atypical Mycobacterial Infection, Familial Disseminated,Atypical Mycobacteriosis, Familial,Atypical Mycobacteriosis, Familial Disseminated,Atypical Mycobacterium Infections,Infections, Atypical Mycobacterium,Mycobacterium abscessus Infection,Atypical Mycobacterium Infection,Familial Atypical Mycobacterioses,Familial Atypical Mycobacteriosis,Infection, Mycobacterium abscessus,Infections, Mycobacterium abscessus,Mycobacterioses, Familial Atypical,Mycobacteriosis, Familial Atypical,Mycobacterium Infection, Atypical,Mycobacterium Infection, Nontuberculous,Mycobacterium abscessus Infections,Nontuberculous Mycobacterium Infection,Nontuberculous Mycobacterium Infections
D009170 Nontuberculous Mycobacteria So-called atypical species of the genus MYCOBACTERIUM that do not cause tuberculosis. They are also called tuberculoid bacilli, i.e.: M. abscessus, M. buruli, M. chelonae, M. duvalii, M. flavescens, M. fortuitum, M. gilvum, M. gordonae, M. intracellulare (see MYCOBACTERIUM AVIUM COMPLEX;), M. kansasii, M. marinum, M. obuense, M. scrofulaceum, M. szulgai, M. terrae, M. ulcerans, M. xenopi. Atypical Mycobacteria,Mycobacteria, Atypical,Mycobacterium duvalii,Mycobacterium flavescens,Mycobacterium gilvum,Mycobacterium gordonae,Mycobacterium obuense,Mycobacterium szulgai,Mycobacterium terrae,Mycolicibacter terrae,Mycolicibacterium duvalii,Mycolicibacterium flavescens,Mycolicibacterium gilvum,Mycolicibacterium obuense,Tuberculoid Bacillus,Atypical Mycobacterium,Mycobacterium, Atypical,Non-Tuberculous Mycobacteria,Nontuberculous Mycobacterium
D000073358 Mycobacterium abscessus A rapidly growing non-tuberculous environmental mycobacterium causing OPPORTUNISTIC INFECTION that infects the skin and subcutaneous tissues. It is associated with HEALTH CARE ASSOCIATED INFECTION and causes serious lung infections in persons with various chronic lung diseases. Mycobacteroides abscessus,Mycobacteroides abscessus subsp. abscessus,Mycobacteroides abscessus subsp. massiliense,Mycobacterium abscessus Complex,Mycobacterium abscessus abscessus,Mycobacterium abscessus bolletii,Mycobacterium abscessus subsp. abscessus,Mycobacterium abscessus subsp. bolletii,Mycobacterium abscessus subspecies abscessus,Mycobacterium abscessus subspecies bolletii,Mycobacterium bolletii,Mycobacterium chelonae abscessus,Mycobacterium massiliense
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000900 Anti-Bacterial Agents Substances that inhibit the growth or reproduction of BACTERIA. Anti-Bacterial Agent,Anti-Bacterial Compound,Anti-Mycobacterial Agent,Antibacterial Agent,Antibiotics,Antimycobacterial Agent,Bacteriocidal Agent,Bacteriocide,Anti-Bacterial Compounds,Anti-Mycobacterial Agents,Antibacterial Agents,Antibiotic,Antimycobacterial Agents,Bacteriocidal Agents,Bacteriocides,Agent, Anti-Bacterial,Agent, Anti-Mycobacterial,Agent, Antibacterial,Agent, Antimycobacterial,Agent, Bacteriocidal,Agents, Anti-Bacterial,Agents, Anti-Mycobacterial,Agents, Antibacterial,Agents, Antimycobacterial,Agents, Bacteriocidal,Anti Bacterial Agent,Anti Bacterial Agents,Anti Bacterial Compound,Anti Bacterial Compounds,Anti Mycobacterial Agent,Anti Mycobacterial Agents,Compound, Anti-Bacterial,Compounds, Anti-Bacterial
D017291 Clarithromycin A semisynthetic macrolide antibiotic derived from ERYTHROMYCIN that is active against a variety of microorganisms. It can inhibit PROTEIN SYNTHESIS in BACTERIA by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. 6-O-Methylerythromycin,A-56268,Biaxin,TE-031,A 56268,A56268,TE 031,TE031
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D017963 Azithromycin A semi-synthetic macrolide antibiotic structurally related to ERYTHROMYCIN. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Azadose,Azithromycin Dihydrate,Azithromycin Monohydrate,Azitrocin,Azythromycin,CP-62993,Goxal,Sumamed,Toraseptol,Ultreon,Vinzam,Zentavion,Zithromax,Zitromax,CP 62993,CP62993,Dihydrate, Azithromycin,Monohydrate, Azithromycin

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