Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
Bioorg Med Chem. 2019 Jan 1;27(1):240-246. doi: 10.1016/j.bmc.2018.12.004. Epub 2018 Dec 5.
Daptomycin, a cyclic lipodepsipeptide antibiotic, has been used clinically since 2003 to treat serious infections caused by Gram-positive bacteria. Although 37 years have passed since daptomycin's discovery, its mechanism of action is still debated. In this report, the effect of replacing the ester bond with an amide bond, and overall stereochemistry, on daptomycin's biological activity was examined. Two peptides were prepared in which the threonine4 residue in the active daptomycin analog, Dap-K6-E12-W13, was replaced with (2S,3R)-diaminobutyric acid ((2S,3R)-DABA) or its epimer (2S,3S-DABA) converting the ring-closing ester bond to an amide bond. Both of these peptides were found to be considerably less active than Dap-K6-E12-W13. These results, along with our previous studies on other daptomycin analogs, enabled us to conclude that the ester bond is crucial to daptomycin's activity. ent-Dap-K6-E12-W13 was found to be at least 133-fold less active than Dap-K6-E12-W13, indicating that a chiral interaction with a chiral target is essential to daptomycin's activity. Studies examining the binding of Dap-K6-E12-W13 and ent-Dap-K6-E12-W13 to model liposomes consisting of phosphatidylglycerol (PG) and phosphatidylcholine suggest that the stereochemistry of PG plays a crucial role in daptomycin-membrane interactions.
达托霉素是一种环状脂肽类抗生素，自 2003 年以来一直用于治疗由革兰氏阳性菌引起的严重感染。虽然达托霉素的发现已经过去了 37 年，但它的作用机制仍存在争议。在本报告中，研究了用酰胺键代替酯键以及整体立体化学对达托霉素生物活性的影响。制备了两种肽，其中活性达托霉素类似物 Dap-K6-E12-W13 中的苏氨酸 4 残基被（2S，3R）-二氨基丁酸（（2S，3R）-DABA）或其差向异构体（2S，3S-DABA）取代，将环闭酯键转化为酰胺键。这两种肽都发现活性明显低于 Dap-K6-E12-W13。这些结果以及我们之前对其他达托霉素类似物的研究使我们能够得出结论，酯键对达托霉素的活性至关重要。内消旋-Dap-K6-E12-W13 的活性至少比 Dap-K6-E12-W13 低 133 倍，表明与手性靶标之间的手性相互作用是达托霉素活性所必需的。研究检查了 Dap-K6-E12-W13 和内消旋-Dap-K6-E12-W13 与由磷脂酰甘油（PG）和磷脂酰胆碱组成的模型脂质体的结合，表明 PG 的立体化学在达托霉素与膜相互作用中起着关键作用。
