Target-Accelerated Combinatorial Synthesis and Discovery of Highly Potent Antibiotics Effective Against Vancomycin-Resistant Bacteria

Abstract

Biological activity can be predicted at a prescreening stage by using a target‐accelerated combinatorial synthesis. The rate of dimerization of vancomycin analogues (see picture, X=CH=CH2, SAc) in the presence of vancomycin's targets Ac‐D‐Ala‐D‐Ala and Ac2‐L‐Lys‐D‐Ala‐D‐Ala correlated well with the observed biological activity. From this study three highly potent antibacterial agents effective against both vancomycin‐susceptible and vancomycin‐resistant bacteria strains were identified.

Protein‐Directed Dynamic Combinatorial Chemistry

“…Nicolaou and coworkers have reported a DCC system based upon dimerization of the highly potent antibiotic vancomycin [ 42 ]. In contrast to the systems described thus far, which involve small -molecule components equilibrating in the presence of a large biological macromolecule (termed casting) [ 7 ], the Nicoloau group examined the effect of small peptide sequences on the dimerization of the much larger vancomycin molecule (molding).…”

Dynamic Combinatorial Chemistry: Ligands for Biomolecules

“…That cell -surface determinants can be targeted with the DCC technique was shown in interesting studies where the bacterial cell wall peptide D -Ala -D -Ala was probed [66,67] . A DCL based on vancomycin -derived components was used and the libraries were made by linking two peptide -binding units by a linker chain.…”

Dynamic Combinatorial Chemistry and Virtual Combinatorial Libraries

“…A recent report describes diversity in macrocyclic structures interconverting through tautomerism [34]. Addition of the D-Ala-D-Ala target leads to amplification and rate acceleration of the formation of specific constituents of a DCL of vancomycin dimers [35]. The relative degree of amplification depends, of course, on the difference in target affinity among the library components.…”