Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS

Frontiers in Pharmacology

卷:12

Marco Scocchi¹  Petar Markov²  Vasil M. Garamus³  Ralf Mikut⁴  Jurnorain Gani⁵  Nathan Simpson⁵  Kai Hilpert⁵  Christoph Rumancev⁶  Axel Rosenhahn⁶  Andreas Robert von Gundlach⁶  Paula Matilde Lopez-Perez⁷ 

[1] Department of Life Sciences, University of Trieste, Trieste, Italy;

[2] European Molecular Biology Laboratory, Hamburg Outstation, Hamburg, Germany;

[3] Helmholtz-Zentrum Hereon, Geesthacht, Germany;

[4] Institute for Automation and Applied Informatics (IAI), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany;

[5] Institute of Infection and Immunology, St. George’s, University of London, London, United Kingdom;

[6] Laboratory Analytical Chemistry - Biointerfaces, Ruhr University Bochum, Bochum, Germany;

[7] TiKa Diagnostics Ltd, London, United Kingdom;

关键词: antimicrobial peptide;    hybrid peptide;    BioSAXS;    multi-drug resistance;    antimicrobial compound;    mode of action;   

DOI  :  10.3389/fphar.2021.769739

来源: DOAJ

【 摘 要 】

Antimicrobial peptides (AMPs) are a promising class of compounds being developed against multi-drug resistant bacteria. Hybridization has been reported to increase antimicrobial activity. Here, two proline-rich peptides (consP1: VRKPPYLPRPRPRPL-CONH2 and Bac5-v291: RWRRPIRRRPIRPPFWR-CONH2) were combined with two arginine-isoleucine-rich peptides (optP1: KIILRIRWR-CONH2 and optP7: KRRVRWIIW-CONH2). Proline-rich antimicrobial peptides (PrAMPs) are known to inhibit the bacterial ribosome, shown also for Bac5-v291, whereas it is hypothesized a “dirty drug” model for the arginine-isoleucine-rich peptides. That hypothesis was underpinned by transmission electron microscopy and biological small-angle X-ray scattering (BioSAXS). The strength of BioSAXS is the power to detect ultrastructural changes in millions of cells in a short time (seconds) in a high-throughput manner. This information can be used to classify antimicrobial compounds into groups according to the ultrastructural changes they inflict on bacteria and how the bacteria react towards that assault. Based on previous studies, this correlates very well with different modes of action. Due to the novelty of this approach direct identification of the target of the antimicrobial compound is not yet fully established, more research is needed. More research is needed to address this limitation. The hybrid peptides showed a stronger antimicrobial activity compared to the proline-rich peptides, except when compared to Bac5-v291 against E. coli. The increase in activity compared to the arginine-isoleucine-rich peptides was up to 6-fold, however, it was not a general increase but was dependent on the combination of peptides and bacteria. BioSAXS experiments revealed that proline-rich peptides and arginine-isoleucine-rich peptides induce very different ultrastructural changes in E. coli, whereas a hybrid peptide (hyP7B5GK) shows changes, different to both parental peptides and the untreated control. These different ultrastructural changes indicated that the mode of action of the parental peptides might be different from each other as well as from the hybrid peptide hyP7B5GK. All peptides showed very low haemolytic activity, some of them showed a 100-fold or larger therapeutic window, demonstrating the potential for further drug development.

【 授权许可】

Unknown