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.
Background Acinetobacter baumannii is a notorious clinical pathogen that predominantly causes nosocomial infections. The multidrug resistant Acinetobacter baumannii clinical isolates are becoming more prevalent on a global scale. In this study, we aimed to determine the potential synergistic antibacterial activity of contezolid in combination with polymyxin B nonapeptide (PBNP) against various A. baumannii strains. Results Contezolid, a commonly-used agents targeting Gram-positive bacteria, in combination with PBNP (CP) was used to explore the potential synergistic antibacterial activity against A. baumannii in vitro and Caenorhabditis elegans models. We found that CP treatment exhibited a strong synergistic effect on A. baumannii or multidrug resistant A. baumannii . CP also inhibited the biofilm formation and alter morphology of A. baumannii compared to the control group. Moreover, the residual bacteria were significantly decreased in the CP-treated murine alveolar macrophages (MH-S). Importantly, CP treatment improved the survival of C. elegans compared to the control or monotherapy group. Conclusions This strategy improved antibacterial activity spectrum of agents targeting Gram-positive bacteria like contezolid. Nevertheless, CP combination therapy requires further validation in mammalian infection models.
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