| Tuberculosis (TB) is one of the most important infectious diseases worldwide up to now. In recent years, increasing incidence of MDR-TB and XDR-TB infections make the situation even worse. Because the existing anti-TB treatment is far from ideal and development of new anti-TB drugs is badly in need.Peptide deformylase (PDF) is an essential metalloenzyme in the prokaryotic protein maturation process, which functions to remove N-terminal formyl from sulfur amino acid residues. This enzyme is required for bacterial survival and growth, while it is not necessary for eukaryotic protein synthesis. Therefore PDF is one of the most promising targets for developing new antibiotic drugs.Microbial secondary metabolites with various chemical structures and biological activities are important sources of new drugs. In our previous work, we screened microbial fermentation samples in China pharmaceutical culture collection using a high-throughput assay for identify PDF inhibitors, and found that the fermentation from Streptomyces CPCC 203702 exhibited potent activity against both MTB and PDF.In this work, we first conducted scale-up fermentation of CPCC 203702 and isolated its secondary metabolites. Guided by anti-M.s (mc2155, CPCC 100246) activity and PDF inhibition activity,13 compounds were isolated by means of normal-phase and reversion-phase silicagel column chromatography, Sephadex LH-20 column chromatography, semi-preparative HPLC, etc. Followed by the structural identification by modern spectroscopy methods, we elucidated 7 compounds. Among them,2482-1, 2482-2 and 2482-3 show anti-M. tuberculosis activity with MIC 2.0 μg/mL,6.8 μg/mL, 2.0 μg/mL respectively. All of the three compounds are classified in Berninamycin. This work, for the first time provides evidence showing that Berninamycin have activity against MTB. Compound 2482-10 shows 53.60% inhibition rate against PDF when its final concentration is 50.0 μg/mL and the structural identification work is in progress. |
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