Optimization of oncocin for antibacterial activity using a SPOT synthesis approach: extending the pathogen spectrum to Staphylococcus aureus

Amino Acids
Daniel KnappeKai Hilpert

Abstract

The identification of lead molecules against multidrug-resistant bacteria ensuing the development of novel antimicrobial drugs is an urgent task. Proline-rich antimicrobial peptides are highly active in vitro and in vivo, but only against a few Gram-negative human pathogens, with rather weak activities against Pseudomonas aeruginosa and Staphylococcus aureus. This reduced level of efficacy could be related to inadequate uptake mechanisms or structural differences of the intracellular target proteins, i.e., the 70S ribosome or chaperone DnaK. Here we synthesized peptide arrays on cellulose membranes using cleavable linkers to release the free individual peptides for further antimicrobial tests. Thus, a library of singly substituted oncocin analogs was produced by replacing each residue by all other 19 canonical amino acids yielding a set of 361 individual peptides to be evaluated against a luminescent P. aeruginosa strain. Thirteen substitutions appeared promising and their improved antibacterial activities were confirmed for different bacteria after larger scale synthesis of these analogs. By combining two favorable substitutions into one peptide, we finally obtained an oncocin analog that was ten times more active against P. a...Continue Reading

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Citations

Jun 19, 2019·Biotechnology and Bioengineering·Pin-Kuang LaiBenjamin J Hackel
Jul 28, 2017·Frontiers in Chemistry·Linda B OyamaSharon A Huws
Jul 19, 2017·Analytical and Bioanalytical Chemistry·Luzia HolfeldDaniel Knappe
May 26, 2017·Natural Product Reports·Michael GrafDaniel N Wilson
Apr 5, 2017·Frontiers in Chemistry·Rico SchmidtRalf Hoffmann
Apr 28, 2017·Frontiers in Chemistry·Paula M López-PérezKai Hilpert
May 21, 2019·Molecular Systems Design & Engineering·Pin-Kuang LaiBenjamin J Hackel
Feb 5, 2021·ACS Nano·Marcelo D T TorresCesar de la Fuente-Nunez
Dec 8, 2020·Biochemistry. Biokhimii︠a︡·Z Z KhairullinaN V Sumbatyan
Sep 11, 2021·ACS Synthetic Biology·Matthew P DeJongBenjamin J Hackel

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