Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens

• Published in: Journal of medicinal chemistry Vol. 58; no. 8; pp. 3340 - 3355
• Main Authors: Fleeman, Renee, LaVoi, Travis M, Santos, Radleigh G, Morales, Angela, Nefzi, Adel, Welmaker, Gregory S, Medina-Franco, José L, Giulianotti, Marc A, Houghten, Richard A, Shaw, Lindsey N
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23-04-2015
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Bacteria - drug effects; Bacterial Infections - drug therapy; Cell Line; Drug Discovery; Guanidines - chemistry; Guanidines - pharmacology; Humans; Mice; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Staphylococcal Infections - drug therapy; Staphylococcus aureus - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501628s

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.