Open AccessCombinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens
Author(s) -
Renee Fleeman,
Travis LaVoi,
Radleigh G. Santos,
Arturo J. Morales,
Adel Nefzi,
Gregory S. Welmaker,
José L. Medina-Franco,
Marc Giulianotti,
Richard A. Houghten,
Lindsey N. Shaw
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm501628s
Subject(s) - chemistry , drug discovery , antibacterial activity , in vivo , in vitro , combinatorial chemistry , broad spectrum , computational biology , bacteria , biochemistry , biology , microbiology and biotechnology , genetics
Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations <2 μM. In addition, these compounds were bactericidal, had antibiofilm effects, showed limited potential for the development of resistance, and displayed almost no toxicity when tested against human lung cells and erythrocytes. Using a murine model of peritonitis, we also demonstrate that these agents are highly efficacious in vivo.