Iterative chemical engineering of vancomycin leads to novel vancomycin analogs with a high in vitro therapeutic index

Vancomycin is a glycopeptide antibiotic that inhibits transpeptidation during cell wall synthesis by binding to the D-Ala-D-Ala termini of lipid II. For long, it has been used as a last resort antibiotic. However, since the emergence of the first vancomycin-resistant enterococci in 1987, vancomycin resistance has become widespread, especially in hospitals. We have synthesized and evaluated 110 vancomycin analogs modified at the C-terminal carboxyl group of the heptapeptide moiety with R2NHR1NH2 substituents. Through iterative optimizations of the substituents, we identified vancomycin analogs that fully restore (or even exceed) the original inhibitory activity against vancomycin-resistant enterococci (VRE), vancomycin-intermediate (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA) strains. The best analogs have improved growth inhibitory activity and in vitro therapeutic indices against a broad set of VRE and methicillin-resistant S. aureus (MRSA) isolates. They also exceed the activity of vancomycin against Clostridium difficile ribotypes. Vanc-39 and Vanc-42 have a low probability to provoke antibiotic resistance, and overcome different vancomycin resistance mechanisms (VanA, VanB, and VanC1). © 2018 Mishra, Stolarzewicz, Cannaerts, Schuermans, Lavigne, Looz, Landuyt, Schoofs, Schols, Paeshuyse, Hickenbotham, Clokie, Luyten, Van der Eycken and Briers.

Mishra N.M.1, 11 , Stolarzewicz I.1, 2 , Cannaerts D.1 , Schuermans J.3 , Lavigne R.3 , Looz Y.4 , Landuyt B.4 , Schoofs L.4 , Schols D.5 , Paeshuyse J.6 , Hickenbotham P.7 , Clokie M.7 , Luyten W.4, 8 , Van Der Eycken E.V. , Briers Y.3, 10
Frontiers Media S.A.
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  • 1 Laboratory for Organic and Microwave-Assisted Chemistry, Department of Chemistry, KU Leuven, Leuven, Belgium
  • 2 Department of Chemistry, Warsaw University of Life Sciences, Warsaw, Poland
  • 3 Laboratory of Gene Technology, Department of Biosystems, KU Leuven, Leuven, Belgium
  • 4 Laboratory of Functional Genomics and Proteomics, Department of Biology, KU Leuven, Leuven, Belgium
  • 5 Laboratory of Virology and Chemotherapy, Rega Institute, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
  • 6 Laboratory for Host Pathogen Interactions, Department of Biosystems, KU Leuven, Leuven, Belgium
  • 7 Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom
  • 8 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
  • 9 Department of Organic Chemistry, Peoples' Friendship University of Russia (RUDN University), Moscow, Russian Federation
  • 10 Laboratory of Applied Biotechnology, Department of Biotechnology, Ghent University, Ghent, Belgium
  • 11 Department of Pharmaceutical Sciences, System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, United States
Ключевые слова
Chemical engineering; In vitro therapeutic index; MRSA; Resistance; Vancomycin analog; VRE
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