rifampin and sansanmycin

Herein, we report the design and synthesis of inhibitors of

Topics: Animals; Antitubercular Agents; Bacterial Proteins; Enzyme Inhibitors; Hydrophobic and Hydrophilic Interactions; Mycobacterium tuberculosis; Oligopeptides; Transferases (Other Substituted Phosphate Groups); Uridine; Zebrafish

Sansanmycins, members of the uridyl peptide antibiotics, are assembled by nonribosomal peptide synthetases (NRPSs), the substrate promiscuity of which results in the diversity of products. Further exploration of the NRPSs' substrate promiscuity by reinvestigating sansanmycin producer strain led to the isolation and structural elucidation of eight new uridyl peptides, sansanmycins H-O (1-8). Among them, sansanmycin L, containing a 6-OH-bicyclic residue and Phe3 first found at the position AA3, exhibited activity against M. tuberculosis H37Rv with an MIC value of 2 μg/mL, 8-fold more potent than that of the major compound, sansanmycin A (MIC = 16 μg/mL).

Topics: Antitubercular Agents; Bacterial Proteins; Molecular Structure; Mycobacterium tuberculosis; Oligopeptides; Peptide Synthases; Streptomyces; Substrate Specificity; Uridine

Tuberculosis (TB) is a major health problem worldwide. A series of novel sansanmycin derivatives were designed, semi-synthesized and evaluated for their activity against drug-susceptible Mycobacterium tuberculosis strain H(37)Rv with sansanmycin A (SSA) as the lead. Among these analogs tested, compound 1d possessing an isopropyl group at the amino terminal afforded an increased antimycobacterial activity with a MIC value of 8 μg/mL in comparison with SSA. Importantly, it was active for rifampicin- and isoniazid-resistant M. tuberculosis strain isolated from patients in China. These promising results offer an opportunity for further exploration of this novel class of analogs as antitubercular agents.

Topics: Antitubercular Agents; China; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oligopeptides; Streptomyces; Tuberculosis; Tuberculosis, Multidrug-Resistant; Uridine