Regiospecific Synthesis of Calcium‐Independent Daptomycin Antibiotics using a Chemoenzymatic Method,Chemistry - A European Journal

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Regiospecific Synthesis of Calcium‐Independent Daptomycin Antibiotics using a Chemoenzymatic Method
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2020-11-26 , DOI: 10.1002/chem.202005100
Nagaraju Mupparapu ₁ , Yu‐Hsin Cindy Lin ₁ , Tae Ho Kim ₁ , Sherif I. Elshahawi ₁

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Daptomycin (DAP) is a calcium (Ca²⁺)‐dependent FDA‐approved antibiotic drug for the treatment of Gram‐positive infections. It possesses a complex pharmacophore hampering derivatization and/or synthesis of analogues. To mimic the Ca²⁺‐binding effect, we used a chemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp‐modified DAP analogues. We demonstrated that the modified DAPs are several times more active than the parent molecule against antibiotic‐susceptible and antibiotic‐resistant Gram‐positive bacteria. Strikingly, and in contrast to the parent molecule, the DAP derivatives do not rely on calcium or any additional elements for activity.

中文翻译：

化学酶法合成钙依赖性达托霉素抗生素的区域特异性

达托霉素（DAP）是FDA批准的钙（Ca ²⁺）依赖性抗生素，用于治疗革兰氏阳性感染。它具有阻碍类似物衍生和/或合成的复杂药效团。为了模拟Ca ^2+的结合作用，我们使用化学酶方法修饰DAP的色氨酸（Trp）残基，并合成动力学表征和结构明确的区域特异性Trp修饰的DAP类似物。我们证明了修饰的DAPs对抗生素敏感性和耐药性革兰氏阳性细菌的活性是其母体分子的几倍。令人惊讶的是，与母体分子相反，DAP衍生物不依赖钙或任何其他元素来发挥作用。

更新日期：2020-11-26

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