Scope and limitations of the designer proline-rich antibacterial peptide dimer, A3-APO, alone or in synergy with conventional antibiotics

Peptides
Marco CassoneLaszlo Otvos

Abstract

The proline-rich antimicrobial peptide dimer, A3-APO, was designed based on a statistical analysis of native antibacterial peptide and protein sequences. Analysis of a series of structural analogs failed to identify any single or multiple amino acid modification or architectural changes that would significantly improve its potential as a clinical therapeutic. However, a single chain Chex1-Arg20 version, a natural in vivo metabolite, showed a 2 to 8-fold increase in activity against test Enterobacteriaceae strains. In addition to bacterial species close to Escherichia coli in phylogeny, A3-APO analogs were able to effectively kill Pseudomonas aeruginosa and Staphylococcus saprophyticus. Antibacterial efficacy analysis together with biochemical experiments provided further evidence for a multiple mode of action of A3-APO that includes binding and inhibition of the bacterial heat shock protein DnaK. Through inactivating of resistance enzymes, A3-APO was able to recover the lost activity of conventional antibiotics including chloramphenicol, beta-lactams, sulfonamides or trimethoprim against multidrug resistant strains with partial or full synergy. However, the synergy appeared to be individual strain and small molecule drug combin...Continue Reading

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Citations

May 20, 2011·Cellular and Molecular Life Sciences : CMLS·Marco ScocchiRenato Gennaro
Jun 5, 2010·Expert Review of Anti-infective Therapy·Marco Cassone, Laszlo Otvos
Jul 18, 2015·Pharmaceuticals·Biljana Mojsoska, Håvard Jenssen
Dec 25, 2013·Bioorganic & Medicinal Chemistry Letters·Victor Hernandez-GordilloJean Chmielewski
Apr 9, 2013·Journal of Molecular Biology·Michael ZahnNorbert Sträter
Oct 21, 2011·Chemical Society Reviews·Søren L PedersenKnud J Jensen
Apr 8, 2018·Applied and Environmental Microbiology·Qian LiOscar P Kuipers
Jul 5, 2017·Frontiers in Chemistry·Laszlo Otvos
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May 5, 2017·European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology·P MoriciA Lupetti
Jul 3, 2013·ACS Synthetic Biology·Katherine VolzingYiannis N Kaznessis

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