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To combat this threat, we rationally designed and synthesized 39 novel vancomycin derivatives by respective or combined modifications using metal\u2010chelating, lipophilic, and galactose\u2010attachment strategies for extensive structure\u2013activity relationship (SAR) analysis. In a proposed mechanism, the conjugation of dipicolylamine on the seventh amino acid resorcinol position or C\u2010terminus endowed the vancomycin backbone with binding capacity for the pyrophosphate moiety in lipid\u2005II while maintaining the intrinsic binding affinity for the dipeptide terminus of the bacterial cell wall peptidoglycan precursor. The in vitro antibacterial activities were evaluated, and the optimal compounds indicated 16\u2010 to 1024\u2010fold higher activity against VRE than that of vancomycin. Compound <jats:bold>11\u2009b<\/jats:bold> (3\u2032,5\u2032\u2010bis(dipicolylaminomethyl)tyrosine [1,2,3]triazolylmethoxylethyoxyl ethylaminomethyl\u2010<jats:italic>N<\/jats:italic>\u2010decylvancomycin) was found to have particularly potent activity against VRE through synergistic effects brought about by combining two peripheral modifications.<\/jats:p>","DOI":"10.1002\/cmdc.201800252","type":"journal-article","created":{"date-parts":[[2018,6,19]],"date-time":"2018-06-19T13:22:14Z","timestamp":1529414534000},"page":"1644-1657","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Design and Synthesis of Pyrophosphate\u2010Targeting Vancomycin Derivatives for Combating Vancomycin\u2010Resistant <i>Enterococci<\/i>"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8561-210X","authenticated-orcid":false,"given":"Dongliang","family":"Guan","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Receptor Research CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Materia Medica Chinese Academy of Sciences  555 Zuchongzhi Road Pudong Shanghai 201203 P.R. 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