Abstract

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.

Highlights

  • In the light of the current headlines of the COVID-19 pandemic, the problem of resistance against antibiotics is still progressing and is frequently called a silent pandemic

  • We investigated E. coli cells treated with optP7 by transmission electron microscopy (TEM) to get a better understanding of the mode of action/ultrastructural changes of the peptides on E. coli, see Figure 1

  • Antimicrobial peptides are a very broad and diverse class of compounds that can kill multi-drug resistant bacteria and have the potential to become the generation of antibiotics

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Summary

Introduction

In the light of the current headlines of the COVID-19 pandemic, the problem of resistance against antibiotics is still progressing and is frequently called a silent pandemic. The beginning of the COVID-19 pandemic demonstrated severely the multitude of effects of an infectious disease where no effective treatment is available. With the emergence of multi-drug resistant strains and a dwindling development of antibacterial drugs with new modes of action, the health care systems worldwide are under threat to face a more severe pandemic if no novel antibiotics are developed. Transplantations, and immunosuppressant therapies may not be performable any longer, leaving modern medicinal care devastated. It is important and urgent to expand the discovery and translation of new alternatives to treat bacterial infections, especially with new modes of action

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