Tripropeptin C Blocks the Lipid Cycle of Cell Wall Biosynthesis by Complex Formation with Undecaprenyl Pyrophosphate
Tripropeptin C Blocks the Lipid Cycle of Cell Wall Biosynthesis by Complex Formation with Undecaprenyl Pyrophosphate
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DOI：
10.1128/aac.00443-11
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发表时间：
2011-08-01
影响因子：
4.9
通讯作者：
Nomoto, Akio
中科院分区：
文献类型：
--
作者：
Hashizume, Hideki;Sawa, Ryuichi;Nomoto, Akio
三肽原C（Tripropeptin C，TPPC）是由溶杆菌属产生的一种天然环状脂缩肽类抗生素，对耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素肠球菌（VRE）和耐青霉素肺炎链球菌（Streptococcus pneumoniae）具有较强的抗菌活性。该抗生素还抑制N-乙酰葡糖胺掺入S.金黄色葡萄球菌的50%抑制浓度（IC（50））为0.7 μ M，其与其MIC（0.87 μ M;相当于1.0 μ g/ml）成比例。指数相S.用TPPC处理金黄色葡萄球菌细胞导致UDP-MurNAc-五肽在细胞质中积累。TPPC的抗微生物活性被减弱的异戊烯基焦磷酸盐，但不被异戊烯基磷酸盐，UDP连接的糖，或肽聚糖的五肽。通过质谱和薄层色谱分析观察到TPPC与十一异戊二烯焦磷酸（C（55）-PP）之间的直接相互作用，表明TPPC可以潜在地抑制C（55）-PP磷酸酶活性，该磷酸酶在肽聚糖合成的脂质循环中起关键作用。正如预期的那样，TPPC在体外抑制这种酶促反应的IC（50）为0.03至0.1 μ M，杆菌肽也是如此。通过对脂质载体相关化合物的蓄积分析，发现TPPC导致C（55）-PP原位蓄积，导致含甘氨酸的脂质中间体蓄积。这表明TPPC/C（55）-PP复合物还抑制转糖基化步骤或翻转酶活性，增加了对C（55）-PP去磷酸化的抑制。这种作用模式不同于目前可用的药物，如万古霉素、达托霉素和杆菌肽。
Tripropeptin C (TPPC) is a naturally occurring cyclic lipodepsipeptide antibiotic produced by a Lysobacter sp. TPPC exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae. This antibiotic also inhibits the incorporation of N-acetylglucosamine into the peptidoglycan of S. aureus at a 50% inhibitory concentration (IC(50)) of 0.7 mu M, which is proportional to its MIC (0.87 mu M; equivalent to 1.0 mu g/ml). Treatment of exponential-phase S. aureus cells with TPPC resulted in accumulation of UDP-MurNAc-pentapeptide in the cytoplasm. The antimicrobial activity of TPPC was weakened by the addition of prenyl pyrophosphates but not by prenyl phosphates, UDP-linked sugars, or the pentapeptide of peptidoglycan. The direct interaction between TPPC and undecaprenyl pyrophosphate (C(55)-PP) was observed by mass spectrometry and thin-layer chromatography analysis, indicating that TPPC can potentially inhibit C(55)-PP phosphatase activity, which plays a crucial role in the lipid cycle of peptidoglycan synthesis. As expected, TPPC inhibits this enzymatic reaction at an IC(50) of 0.03 to 0.1 mu M in vitro, as does bacitracin. From the analysis of accumulation of lipid carrier-related compounds, TPPC was found to cause the accumulation of C(55)-PP in situ, leading to the accumulation of a glycine-containing lipid intermediate. This suggested that the TPPC/C(55)-PP complex also inhibits the transglycosylation step or flippase activity, adding to the inhibition of C(55)-PP dephosphorylation. This mode of action is different from that of currently available drugs such as vancomycin, daptomycin, and bacitracin.