Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification.,ACS Infectious Diseases

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Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-06-29 , DOI: 10.1021/acsinfecdis.0c00258
Zhi-Chen Wu ₁ , Michael D Cameron ₂ , Dale L Boger ₁

Affiliation

A series of vancomycin C-terminus guanidine modifications is disclosed that improves antimicrobial activity, enhances the durability of antimicrobial action against selection or induction of resistance, and introduces a synergistic mechanism of action independent of d-Ala-d-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compounds examined that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive but especially vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of d-Ala-d-Ala/d-Lac binding and display superb antimicrobial potencies (MIC 0.6–0.15 μg/mL, VanA VRE). For the first time, we demonstrate that the synergistic behavior of the peripheral modifications examined requires the presence of both the CBP and guanidine modifications in a single molecule versus their combined use as an equimolar mixture of singly modified compounds. Finally, we show that a prototypical member of the series, G3-CBP-vancomycin (15), exhibits no hemolytic activity, displays no mammalian cell growth inhibition, possesses improved and especially attractive in vivo pharmacokinetic (PK) properties, and displays excellent in vivo efficacy and potency against an especially challenging multidrug-resistant (MRSA) and VanA vancomycin-resistant (VRSA) Staphylococcus aureus bacterial strain.

中文翻译：

万古霉素 C 端胍修饰和对由外周结构修饰赋予的附加作用机制的进一步见解。

公开了一系列万古霉素 C 端胍修饰，可提高抗微生物活性，增强抗选择或诱导抗性的抗微生物作用的持久性，并引入独立于d -Ala- d的协同作用机制-Ala 结合和抑制细胞壁生物合成。添加的作用机制导致诱导的细菌细胞通透性，我们表明这可能涉及与细胞包膜磷壁酸的相互作用。值得注意的是，所检测的化合物包含两种组合外周修饰，即（4-氯联苯）甲基（CBP）和 C 端胍修饰，为新疗法提供了机会，不仅针对万古霉素敏感的细菌，尤其是针对万古霉素耐药的细菌，它们通过以下方式发挥作用：两种独立于d -Ala- d -Ala/ d 的协同且持久的作用机制- Lac 结合并显示出极好的抗菌效力（MIC 0.6–0.15 μg/mL，VanA VRE）。我们第一次证明了所检查的外周修饰的协同行为需要在单个分子中同时存在 CBP 和胍修饰，而不是它们作为单一修饰化合物的等摩尔混合物的组合使用。最后，我们展示了该系列的典型成员 G3-CBP-万古霉素 ( 15 )，不显示溶血活性，不显示哺乳动物细胞生长抑制，具有改进且特别有吸引力的体内药代动力学 (PK) 特性，并在针对特别具有挑战性的多重耐药性 (MRSA) 和 VanA 万古霉素耐药性 (VRSA) 的体内功效和效力金黄色葡萄球菌菌株。

更新日期：2020-08-14

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