Targeting Vancomycin-Resistant Enterococci (VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid–Peptide Conjugates,Journal of Medicinal Chemistry

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Targeting Vancomycin-Resistant Enterococci (VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid–Peptide Conjugates
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-04 , DOI: 10.1021/acs.jmedchem.2c01293
Varsha Saini ₁ , Devashish Mehta ₁ , Siddhi Gupta ₁ , Sandeep Kumar ₁ , Parul Rani ₁ , Kajal Rana ₁ , Kajal Rajput ₁ , Dolly Jain ₁ , Garima Pal ₂ , Bharti Aggarwal ₁ , Sanjay Pal ₁ , Sonu K Gupta ₃ , Yashwant Kumar ₃ , Vemanna S Ramu ₂ , Avinash Bajaj ₁

Affiliation

Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant Enterococci (VRE) infections are highly alarming as very limited antibiotic options are available against VRE infections. Here, we present the synthesis of cholic acid-derived dimeric amphiphiles where two cholic acid moieties are tethered through carboxyl terminals using different alkylene spacers. Our investigations revealed that dimer 5 possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE. Dimer 5 can permeabilize bacterial membranes, generate reactive oxygen species, and clear preformed biofilms. We further demonstrate that dimer 5 downregulates vancomycin-mediated transcriptional activation of the vanHAX gene cluster and does not allow VSE to develop vancomycin resistance until 100 generations. Therefore, this study, for the first time, presents a bacterial membrane-targeting amphiphile that can mitigate VRE infections and inhibit the emergence of vancomycin resistance.

中文翻译：

使用二聚胆酸-肽偶联物靶向耐万古霉素肠球菌 (VRE) 感染和 Van Operon 介导的耐药性

革兰氏阳性菌对万古霉素耐药性的出现以及耐万古霉素肠球菌(VRE) 感染的流行非常令人担忧，因为针对 VRE 感染的抗生素选择非常有限。在这里，我们介绍了胆酸衍生的二聚两亲物的合成，其中两个胆酸部分使用不同的亚烷基间隔物通过羧基末端连接。我们的研究表明，具有丙烯间隔区和拴在羟基上的甘氨酸缬氨酸肽的二聚体5是对抗 VRE 最有效的抗菌剂。二聚体5可以透化细菌膜，产生活性氧，并清除预先形成的生物膜。我们进一步证明二聚体5下调万古霉素介导的 vanHAX 基因簇的转录激活，直到 100 代后才允许 VSE 产生万古霉素抗性。因此，本研究首次提出了一种可以减轻 VRE 感染并抑制万古霉素耐药性出现的细菌膜靶向两亲物。

更新日期：2022-11-04

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