Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase

To combat the threat of antibiotic-resistant Gram-negative bacteria, novel agents that circumvent established resistance mechanisms are urgently needed. Our approach was to focus first on identifying bioactive small molecules followed by chemical lead prioritization and target identification. Within...

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Bibliographic Details
Published in:PloS one 2017-07, Vol.12 (7), p.e0180965-e0180965
Main Authors: Walker, Scott S, Labroli, Marc, Painter, Ronald E, Wiltsie, Judyann, Sherborne, Brad, Murgolo, Nicholas, Sher, Xinwei, Mann, Paul, Zuck, Paul, Garlisi, Charles G, Su, Jing, Kargman, Stacia, Xiao, Li, Scapin, Giovanna, Salowe, Scott, Devito, Kristine, Sheth, Payal, Buist, Nichole, Tan, Christopher M, Black, Todd A, Roemer, Terry
Format: Article
Language:English
Subjects:
Acid resistance
Amino acids
Anti-Bacterial Agents - pharmacology
Antibacterial agents
Antibiotic resistance
Antibiotics
Antiinfectives and antibacterials
Antimicrobial agents
Bacteria
Bacterial infections
Binding sites
Biocompatibility
Biology and Life Sciences
Biomedical materials
Biosynthesis
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA Gyrase - metabolism
DNA replication
DNA topoisomerase
Drug Resistance, Bacterial - genetics
E coli
Efflux
Enzymes
Escherichia coli
Escherichia coli - drug effects
Escherichia coli - enzymology
Fluoroquinolones
Fluoroquinolones - pharmacology
Genomes
Gram-negative bacteria
Infections
Inhibition
Inhibitor drugs
Inhibitors
Libraries
Medicine and Health Sciences
Microbial drug resistance
Microbial Sensitivity Tests
Mutation
Physical sciences
Protein Domains
Pseudomonas
Pseudomonas aeruginosa
Pseudomonas aeruginosa - drug effects
Pseudomonas aeruginosa - enzymology
Replication
Research and Analysis Methods
Stabilization
Surgical implants
Target recognition
Topoisomerase I
Topoisomerase II Inhibitors - pharmacology
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Summary:To combat the threat of antibiotic-resistant Gram-negative bacteria, novel agents that circumvent established resistance mechanisms are urgently needed. Our approach was to focus first on identifying bioactive small molecules followed by chemical lead prioritization and target identification. Within this annotated library of bioactives, we identified a small molecule with activity against efflux-deficient Escherichia coli and other sensitized Gram-negatives. Further studies suggested that this compound inhibited DNA replication and selection for resistance identified mutations in a subunit of E. coli DNA gyrase, a type II topoisomerase. Our initial compound demonstrated weak inhibition of DNA gyrase activity while optimized compounds demonstrated significantly improved inhibition of E. coli and Pseudomonas aeruginosa DNA gyrase and caused cleaved complex stabilization, a hallmark of certain bactericidal DNA gyrase inhibitors. Amino acid substitutions conferring resistance to this new class of DNA gyrase inhibitors reside exclusively in the TOPRIM domain of GyrB and are not associated with resistance to the fluoroquinolones, suggesting a novel binding site for a gyrase inhibitor.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0180965