AUTHOR=Mishra Nigam M. , Stolarzewicz Izabela , Cannaerts David , Schuermans Joris , Lavigne Rob , Looz Yannick , Landuyt Bart , Schoofs Liliane , Schols Dominique , Paeshuyse Jan , Hickenbotham Peter , Clokie Martha , Luyten Walter , Van der Eycken Erik V. , Briers Yves 

TITLE=Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.01175

DOI=10.3389/fmicb.2018.01175

ISSN=1664-302X

ABSTRACT=<p>Vancomycin is a glycopeptide antibiotic that inhibits transpeptidation during cell wall synthesis by binding to the <sc>D</sc>-Ala-<sc>D</sc>-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 R<sub>2</sub>NHR<sub>1</sub>NH<sub>2</sub> 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 <italic>Staphylococcus aureus</italic> (VRSA) strains. The best analogs have improved growth inhibitory activity and <italic>in vitro</italic> therapeutic indices against a broad set of VRE and methicillin-resistant <italic>S. aureus</italic> (MRSA) isolates. They also exceed the activity of vancomycin against <italic>Clostridium difficile</italic> ribotypes. Vanc-39 and Vanc-42 have a low probability to provoke antibiotic resistance, and overcome different vancomycin resistance mechanisms (VanA, VanB, and VanC1).</p>