Mycobacterium abscessus is a fast-growing nontuberculous mycobacterium that can cause severe disease and poses a significant challenge for clinical management. New drugs are urgently needed for more effective treatment. Nitroxoline, an antibiotic used for treating urinary tract infections in Europe, has recently been shown to have promising activity against M. abscessus. However, the mechanism of its modified activity is not known. In anticipation for its potential clinical use, in this study, we investigated the mechanism of nitroxoline activity modification through mutant selection followed by whole-genome sequencing. We identified mutations in a transcriptional repressor MarR (MAB_2648c) controlling the expression of efflux pumps MmpS5-MmpL5 family that are associated with nitroxoline activity modification. Complementation of the mutants with the wild-type marR gene restored the MIC values to levels comparable to those of the wild-type strain. This study elucidates the key mechanism of how M. abscessus mutations modify the activity of nitroxoline, which has significant implications for rapid molecular detection of drug-resistant M. abscessus and for further studies on resistance mechanisms.
Objective To evaluate contezolid (MRX-I) antibacterial activity against Mycobacterium abscessus in vitro and in vivo and to assess whether MRX-I treatment can prolong survival of infected zebrafish. Methods MRX-I inhibitory activity against M. abscessus in vitro was assessed by injecting MRX-I into zebrafish infected with green fluorescent protein-labelled M. abscessus . Thereafter, infected zebrafish were treated with azithromycin (AZM), linezolid (LZD) or MRX-I then maximum tolerated concentrations (MTCs) of drugs were determined based on M. abscessus growth inhibition using one-way ANOVA. Linear trend analysis of CFU counts and fluorescence intensities (mean ± SE values) was performed to detect linear relationships between MRX-I, AZM and LZD concentrations and these parameters. Results MRX-I anti- M. abscessus minimum inhibitory concentration (MIC) and MTC were 16 μg/mL and 15.6 μg/mL, respectively. MRX-I MTC-treated zebrafish fluorescence intensities were significantly lower than respective LZD group intensities (whole-body: 439040 ± 3647 vs. 509184 ± 23064, p < 0.01); head: 74147 ± 2175 vs. 95996 ± 8054, p < 0.05). As MRX-I concentration was increased from 0.488 μg/mL to 15.6 μg/mL, zebrafish whole-body, head and heart fluorescence intensities decreased. Statistically insignificant differences between the MRX-I MTC group survival rate (78.33%) vs. corresponding rates of the 62.5 μg/mL-treated AZM MTC group (88.33%, p > 0.05) and the 15.6 μg/mL-treated LZD MTC group (76.67%, p > 0.05) were observed. Conclusion MRX-I effectively inhibited M. abscessus growth and prolonged zebrafish survival when administered to M. abscessus -infected zebrafish, thus demonstrating that MRX-I holds promise as a clinical treatment for human M. abscessus infections.
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