New inhibitors of bacterial protein synthesis from a combinatorial library of macrocycles.
A mixture-based combinatorial library of 14-membered macrocycles was synthesized to target ribosomal RNA and uncover a new class of antibacterial agents. High-throughput screening identified a macrocyclic mixture that inhibited cell-free-coupled transcription/translation in Escherichia coli-derived extracts, with an IC(50) value in the 25-50 microM range. In a follow-up library of 64 single macrocycles, 8 gave IC(50) values ranging from 12 to 50 microM in the cell-free protein synthesis inhibition assay. Some of the macrocycles were screened in a translation inhibition assay, and IC(50) values generally paralleled those obtained in the uncoupled transcription/translation assay. Additional analogues were prepared in a preliminary structure-activity relationship study, and more potent macrocycles were identified with low micromolar activity (IC(50) values = 2-3 microM). Some of these macrocycles displayed antibacterial activity against lipopolysaccharide mutant E. coli bacterial cells (IC(50) values = 12-50 microM).
Ibis Therapeutics, A Division of Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008, USA. ejeffers@isisph.com
Elizabeth A
EA
Jefferson
Satoshi
S
Arakawa
Lawrence B
LB
Blyn
Alycia
A
Miyaji
Stephen A
SA
Osgood
Raymond
R
Ranken
Lisa M
LM
Risen
Eric E
EE
Swayze
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020650:Combinatorial Chemistry Techniques; D004926:Escherichia coli / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000737:chemistry; D009154:Mutation; D014176:Protein Biosynthesis / Q000187:drug effects; D011810:Quinoxalines / Q000737:chemistry; D012329:RNA, Bacterial / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006571:Heterocyclic Compounds; D008070:Lipopolysaccharides; D011810:Quinoxalines; D012329:RNA, Bacterial; D012335:RNA, Ribosomal