Saini Varsha, Mehta Devashish, Gupta Siddhi, Kumar Sandeep, Rani Parul, Rana Kajal, Rajput Kajal, Jain Dolly, Pal Garima, Aggarwal Bharti, Pal Sanjay, Gupta Sonu K, Kumar Yashwant, Ramu Vemanna S, Bajaj Avinash
Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad 121001, Haryana, India.
Laboratory of Plant Functional Genomics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad 121001, Haryana, India.
J Med Chem. 2022 Nov 24;65(22):15312-15326. doi: 10.1021/acs.jmedchem.2c01293. Epub 2022 Nov 4.
Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant (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 possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE. Dimer can permeabilize bacterial membranes, generate reactive oxygen species, and clear preformed biofilms. We further demonstrate that dimer 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.
革兰氏阳性菌中万古霉素耐药性的出现以及耐万古霉素肠球菌（VRE）感染的流行令人高度担忧，因为针对VRE感染的抗生素选择非常有限。在此，我们展示了胆酸衍生的二聚两亲分子的合成，其中两个胆酸部分通过羧基末端使用不同的亚烷基间隔基相连。我们的研究表明，具有丙烯间隔基且羟基上连接有甘氨酸 - 缬氨酸肽的二聚体是针对VRE最有效的抗菌剂。二聚体可以使细菌膜通透化，产生活性氧，并清除预先形成的生物膜。我们进一步证明，二聚体下调万古霉素介导的vanHAX基因簇的转录激活，并且在100代之前不允许VSE产生万古霉素耐药性。因此，本研究首次提出了一种靶向细菌膜的两亲分子，它可以减轻VRE感染并抑制万古霉素耐药性的出现。
