Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.
Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.
复制标题
塑造牛体连接的万古霉素二聚体作为抗多药耐药革兰氏阳性细菌的有效抗生素。
DOI：
10.1073/pnas.2208737120
复制
发表时间：
2023-04-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
多重耐药细菌的迅速出现是对全球公共卫生的最大威胁之一，需要快速提供新疗法来挽救患者的生命。然而，新药类别的开发和临床推广是一个缓慢的过程，不太可能及时解决这场危机。对临床批准的抗生素进行重新设计以逃避耐药机制，提供了一种潜在的近短期解决方案，该解决方案利用了现有的供应链和临床成功。本着这种精神，我们设计并合成了一类独特的变形万古霉素二聚体，可以逃避耐药性的获得，为未来研究变形抗生素药物铺平道路，以帮助对抗耐药病原体——包括致命的万古霉素和耐甲氧西林金黄色葡萄球菌。对最后手段耐药的超级细菌（包括耐万古霉素肠球菌和葡萄球菌）数量惊人增加，已成为严重的全球健康危害。在此，我们报告了前所未有的一类变形万古霉素二聚体（SVD）的点击化学合成，该二聚体对对母体药物具有耐药性的细菌表现出强大的活性，包括 ESKAPE 病原体、耐万古霉素肠球菌（VRE）、耐甲氧西林金黄色葡萄球菌（MRSA）以及耐万古霉素金黄色葡萄球菌（VRSA）。二聚体的变形方式由三唑连接的 Bullvalene 核心提供动力，利用流动碳笼的动态共价重排并创建具有抑制细菌细胞壁生物合成能力的配体。新的变形抗生素不会因 C 末端二肽被相应的 d-Ala-d-Lac 缩酚肽改变而导致万古霉素耐药的常见机制处于不利地位。此外，有证据表明，变形配体破坏了翻转酶 MurJ 和脂质 II 之间形成的复合物的稳定性，这意味着多价糖肽有可能出现一种新的作用模式。 SVD 表现出肠球菌几乎不产生获得性耐药性，这表明这种新型变形抗生素将表现出持久的抗菌活性，不易迅速获得临床耐药性。
The rapid emergence of multidrug-resistant bacteria is one of the greatest threats to global public health, demanding rapid delivery of new therapies to save patient lives. However, the development and clinical rollout of novel drug classes is a slow process that is unlikely to deliver a timely solution to this crisis. The reengineering of clinically approved antibiotics to evade resistance mechanisms offers a potential near- to short-term solution that takes advantage of established supply chains and clinical success. In this vein, we have designed and synthesized a unique class of shapeshifting vancomycin dimers that evade resistance acquisition, paving the way for future studies into shapeshifting antibiotic drugs to aid in the fight against resistant pathogens — including deadly VRE and MRSA. The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
登录
查看更多内容
影响因子：
18.3
作者：
Chang M;Mahasenan KV;Hermoso JA;Mobashery S
通讯作者：
Mobashery S
影响因子：
15
作者：
Jain, RK;Trias, J;Ellman, JA
通讯作者：
Ellman, JA
影响因子：
16.6
作者：
Blaskovich MAT;Hansford KA;Gong Y;Butler MS;Muldoon C;Huang JX;Ramu S;Silva AB;Cheng M;Kavanagh AM;Ziora Z;Premraj R;Lindahl F;Bradford TA;Lee JC;Karoli T;Pelingon R;Edwards DJ;Amado M;Elliott AG;Phetsang W;Daud NH;Deecke JE;Sidjabat HE;Ramaologa S;Zuegg J;Betley JR;Beevers APG;Smith RAG;Roberts JA;Paterson DL;Cooper MA
通讯作者：
Cooper MA
影响因子：
5.3
作者：
Blaskovich MAT;Hansford KA;Butler MS;Jia Z;Mark AE;Cooper MA
通讯作者：
Cooper MA
影响因子：
7.3
作者：
Dhanda, Geetika;Sarkar, Paramita;Haldar, Jayanta
通讯作者：
Haldar, Jayanta