Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
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The widespread emergence of multidrug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) is a high threat for human health. In the course of screening for active compounds against the above drug-resistant bacteria from microbial metabolites, we discovered three kinds of novel compounds designated tripropeptins, pargamicin, and amycolamicin. Tripropeptin C (TPPC), major component of tripropeptins, is the most promising compound because it is efficacious against MRSA and VRE both in vitro and in a mouse septicemia model, and shows no cross-resistance to available drugs including vancomycin. ⋯ Direct interaction between TPPC and undecaprenyl pyrophosphate (C(55)-PP) was observed by mass spectrometry and thin layer chromatography, and TPPC inhibits C(55)-PP phosphatase, which plays a crucial role in peptidoglycan synthesis at an IC(50) of 0.03-0.1 µM in vitro. From the analysis of accumulation of lipid carrier-related compounds, TPPC caused accumulation of C(55)-PP in situ, leading to the accumulation of a glycine-added lipid intermediate, suggesting a distinct mode of action from that of clinically important drugs such as vancomycin, daptomycin, and bacitracin. TPPC might represent a promising novel class of antibiotic against MRSA and VRE infections.