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Ribosomal Target-Binding Sites of Antimicrobial Peptides Api137 and Onc112 Are Conserved among Pathogens Indicating New Lead Structures To Develop Novel Broad-Spectrum Antibiotics.


ABSTRACT: Proline-rich antimicrobial peptides expressed in insects are primarily active against Enterobacteriaceae. Mechanistically, they target the bacterial (70S) ribosome after partially transporter-based cellular uptake, as revealed for Api137 and Onc112 on Escherichia coli. Following molecular modeling indicating that the Onc112 contact site is conserved among the ribosomes of high-priority pathogens, the ribosome binding of Api137 and Onc112 was studied. The dissociation constants (Kd ) of Onc112 were ?75?nmol/L for Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, 36?nmol/L for Pseudomonas aeruginosa, and 102?nmol/L for Staphylococcus aureus, thus indicating a very promising lead structure for developing broad-spectrum antibiotics. Api137 bound weaker with Kd values ranging from 155?nmol/L to 13??mol/L. For most bacteria, the antibacterial activities were lower than predicted from the Kd values, which was only partially explained by their ability to enter bacterial cells. Other factors limiting the activity expected from the ribosome binding might be off-target binding.

SUBMITTER: Kolano L 

PROVIDER: S-EPMC7540576 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Ribosomal Target-Binding Sites of Antimicrobial Peptides Api137 and Onc112 Are Conserved among Pathogens Indicating New Lead Structures To Develop Novel Broad-Spectrum Antibiotics.

Kolano Lisa L   Knappe Daniel D   Volke Daniela D   Sträter Norbert N   Hoffmann Ralf R  

Chembiochem : a European journal of chemical biology 20200630 18


Proline-rich antimicrobial peptides expressed in insects are primarily active against Enterobacteriaceae. Mechanistically, they target the bacterial (70S) ribosome after partially transporter-based cellular uptake, as revealed for Api137 and Onc112 on Escherichia coli. Following molecular modeling indicating that the Onc112 contact site is conserved among the ribosomes of high-priority pathogens, the ribosome binding of Api137 and Onc112 was studied. The dissociation constants (K<sub>d</sub> ) o  ...[more]

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