Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560064, Karnataka, India.
Angew Chem Int Ed Engl. 2016 Jun 27;55(27):7836-40. doi: 10.1002/anie.201601621. Epub 2016 Mar 24.
Vancomycin, the drug of last resort for Gram-positive bacterial infections, has also been rendered ineffective by the emergence of resistance in such bacteria. To combat the threat of vancomycin-resistant bacteria (VRB), we report the development of a dipicolyl-vancomycin conjugate (Dipi-van), which leads to enhanced inhibition of cell-wall biosynthesis in VRB and displays in vitro activity that is more than two orders of magnitude higher than that of vancomycin. Conjugation of the dipicolyl moiety, which is a zinc-binding ligand, endowed the parent drug with the ability to bind to pyrophosphate groups of cell-wall lipids while maintaining the inherent binding affinity for pentapeptide termini of cell-wall precursors. Furthermore, no detectable resistance was observed after several serial passages, and the compound reduced the bacterial burden by a factor of 5 logs at 12 mg kg(-1) in a murine model of VRB kidney infection. The findings presented in this report stress the potential of our strategy to combat VRB infections.
万古霉素是治疗革兰氏阳性菌感染的最后手段，但由于此类细菌产生了耐药性，万古霉素也失去了疗效。为了应对耐万古霉素细菌（VRB）的威胁，我们报告了一种二吡啶基-万古霉素缀合物（Dipi-van）的开发，它导致 VRB 细胞壁生物合成的抑制增强，并且在体外活性比万古霉素高两个数量级以上。二吡啶基部分的缀合是一种锌结合配体，使母体药物具有与细胞壁脂质的焦磷酸基团结合的能力，同时保持对细胞壁前体五肽末端的固有结合亲和力。此外，在多次连续传代后没有观察到耐药性，并且该化合物在 VRB 肾脏感染的小鼠模型中以 12mg/kg 的剂量降低了 5 个对数级的细菌负荷。本报告中提出的研究结果强调了我们的策略在对抗 VRB 感染方面的潜力。
