Structure-guided discovery of novel aminoglycoside mimetics as antibacterial translation inhibitors.
We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.
Zhou
Yuefen
Y
Anadys Pharmaceuticals, San Diego, California, USA.
Gregor
Vlad E
VE
Sun
Zhongxiang
Z
Ayida
Benjamin K
BK
Winters
Geoffrey C
GC
Murphy
Douglas
D
Simonsen
Klaus B
KB
Vourloumis
Dionisios
D
Fish
Sarah
S
Froelich
Jamie M
JM
Wall
Daniel
D
Hermann
Thomas
T
D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011487:Protein Conformation; D012270:Ribosomes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000494:pharmacology
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D010880:Piperidines; D014227:Triazines