[Studies for the development of novel anti-MRSA/VRE drugs].
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. Studies of incorporation of radioactive macromolecular precursors and accumulation of UDP-MurNAc-pentapeptide in the cytoplasm in S. aureus Smith revealed that TPPC is a cell wall synthesis inhibitor. Antimicrobial activity of TPPC was weakened by addition of prenylpyrophosphates but not with prenylphosphates, UDP-linked sugars, or the pentapeptide of peptidoglycan. 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.
Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan. hashizumeh@bikaken.or.jp
Hideki
H
Hashizume
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D047630:Depsipeptides / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D016983:Enterococcus / Q000187:drug effects*; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D011106:Polyisoprenyl Phosphates / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy; D020713:Vancomycin Resistance / Q000187:drug effects
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D005960:Glucosides; D010456:Peptides, Cyclic; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; C548730:amycolamicin; C532991:pargamicin A; C535087:tripropeptin aiC; C009621:undecaprenyl phosphate