This study aimed to evaluate the in vitro antimicrobial activity, heteroresistance emergence, and resistance mechanism of omadacycline (OMC) in clinical Enterococcus faecalis isolates from China. A total of 276 isolates were collected retrospectively in China from 2011 to 2015. The MICs of OMC, doxycycline (DOX), and minocycline (MIN) against E. faecalis were determined by broth microdilution. Tetracycline (TET)-specific resistance genes and multilocus sequence typing (MLST) of the isolates were investigated using PCR. The detection frequency of OMC heteroresistance in E. faecalis was evaluated with population analysis profiling (PAP). The mechanism of OMC heteroresistance and resistance in E. faecalis was examined by amplifying 30S ribosomal subunit genes, RNA sequencing (RNA-Seq), and in vitro recombination experiments. The OMC MICs of clinical E. faecalis isolates ranged from ≤0.06 to 1.0 mg/liter, and 42% of the E. faecalis isolates with an OMC MIC of 1.0 mg/liter were found to be sequence type 16 (ST16). Six OMC-heteroresistant isolates with MIC values of ≤0.5 mg/liter were detected among 238 E. faecalis isolates. The resistant subpopulations of heteroresistant isolates showed OMC MICs in the range of 2 to 4 mg/liter and were found without 30S ribosomal subunit gene mutations. Moreover, RNA sequencing and in vitro recombination experiments demonstrated that overexpression of a bone morphogenetic protein (BMP) family ATP-binding cassette (ABC) transporter substrate-binding protein, OG1RF_RS00630, facilitated OMC heteroresistance in E. faecalis. In conclusion, OMC exhibited better activity against clinical E. faecalis isolates from China than that of DOX or MIN, and overexpression of OG1RF_RS00630 in E. faecalis facilitated the development of OMC heteroresistance.
Cucumber target spot, a major disease that threatens cucumber production, is caused by Corynespora cassiicola . Cyclobutrifluram, a novel succinate dehydrogenase inhibitor (SDHI) developed by Syngenta, has demonstrated strong inhibitory activity against various plant pathogenic fungi and nematodes. However, its antifungal spectrum, resistance risk as well as underlying mechanisms of resistance in C. cassiicola remain poorly understood. In this study, cyclobutrifluram exhibited potent inhibitory activity against anamorphic fungi and selected ascomycetes, with the mean sensitivity of C. cassiicola isolates to the fungicide being 0.98 ± 1.26 μg/mL. Additionally, five laboratory-derived cyclobutrifluram-resistant mutants showed comparable or lower biological fitness than their respective parental isolates. The resistant mutants and field isolates were also found to possess nine distinct point mutations in the CcSdhB , CcSdhC or CcSdhD genes. Finally, cyclobutrifluram exhibited positive cross-resistance with other SDHIs, with the resistance levels varying depending on the specific mutations present. In conclusion, cyclobutrifluram was found to be effective against anamorphic fungi and selected ascomycetes. C. cassiicola ’s risk of resistance development to cyclobutrifluram was assessed as moderate to high and was primarily associated with mutations in CcSdh genes.
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