Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones-targeting virulence of uropathogenic E. coli.
Substituted bicyclic 2-pyridones, termed pilicides, are dipeptide mimetics that prevent pilus assembly in uropathogenic Escherichia coli. Here, we apply rational design to produce four classes of extended peptidomimetics based on two bioactive 2-pyridones. The key intermediate in the synthesis was an amino-functionalised 2-pyridone scaffold, which could be obtained via a mild and selective nitration and subsequent reduction. Procedures were then developed to further derivatize this amino-substituted core and a total of 24 extended peptidomimetics were synthesised and evaluated for chaperone affinity and in vivo antivirulence activity in P pili producing E. coli. Enhanced affinities for the target protein were observed within the generated set of compounds, while the ability to prevent pilus assembly in vivo was significantly decreased compared to the parent lead compounds. The results suggest that the limited in vivo potencies of the analogues are either uptake/distribution related or due to loss in binding specificity.
Berg
Veronica
V
Organic Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Sellstedt
Magnus
M
Hedenström
Mattias
M
Pinkner
Jerome S
JS
Hultgren
Scott J
SJ
Almqvist
Fredrik
F
D032701:Biomimetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects* / Q000472:pathogenicity*; D009682:Magnetic Resonance Spectroscopy; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011728:Pyridones / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014551:Urinary Tract / Q000382:microbiology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018832:Molecular Chaperones; D010455:Peptides; D011728:Pyridones