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Vancomycin was long considered immune to resistance due to its bactericidal activity based on binding to the bacterial cell envelope rather than to a protein target as is the case for most antibiotics. However, two types of complex resistance mechanisms, each comprised of a multi\u2010enzyme pathway, emerged and are now widely disseminated in pathogenic species, thus threatening the clinical efficiency of vancomycin. Vancomycin forms an intricate network of hydrogen bonds with the\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Ala\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Ala region of Lipid II, interfering with the peptidoglycan layer maturation process. Resistance to vancomycin involves degradation of this natural precursor and its replacement with\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Ala\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010lac or\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Ala\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Ser alternatives to which vancomycin has low affinity. Through extensive research over 30\u2009years after the initial discovery of vancomycin resistance, remarkable progress has been made in molecular understanding of the enzymatic cascades responsible. Progress has been driven by structural studies of the key components of the resistance mechanisms which provided important molecular understanding such as, for example, the ability of this cascade to discriminate between vancomycin sensitive and resistant peptidoglycan precursors. Important structural insights have been also made into the molecular evolution of vancomycin resistance enzymes. Altogether this molecular data can accelerate inhibitor discovery and optimization efforts to reverse vancomycin resistance. Here, we overview our current understanding of this complex resistance mechanism with a focus on the structural and molecular aspects.\n                  <\/jats:p>","DOI":"10.1002\/pro.3819","type":"journal-article","created":{"date-parts":[[2020,1,3]],"date-time":"2020-01-03T11:21:17Z","timestamp":1578050477000},"page":"654-669","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":379,"title":["Molecular mechanisms of vancomycin resistance"],"prefix":"10.1002","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8663-1425","authenticated-orcid":false,"given":"Peter J.","family":"Stogios","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering and Applied Chemistry University of Toronto  Toronto Ontario Canada"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-9237","authenticated-orcid":false,"given":"Alexei","family":"Savchenko","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Applied Chemistry University of Toronto  Toronto Ontario Canada"},{"name":"Center for Structural Genomics of Infectious Diseases (CSGID)"},{"name":"Department of Microbiology, Immunology and Infectious Diseases University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,23]]},"reference":[{"key":"e_1_2_4_2_1","unstructured":"CDC(2013) Antibiotic Resistance Threats in the United States 2013."},{"key":"e_1_2_4_3_1","unstructured":"World Health Organization (WHO). 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