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Antibacterial Properties and Efficacy of LL-37 Fragment GF-17D3 and Scolopendin A2 Peptides Against Resistant Clinical Strains of Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii In Vitro and In Vivo Model Studies

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Abstract

Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii have emerged as major clinical threats owing to the increasing prevalence of ventilator-associated pneumonia caused by multidrug-resistant or extensively drug-resistant strains. The present study aimed to assess the antibacterial effects and efficacy of LL-37 fragment GF-17D3 and synthetic Scolopendin A2 peptides against resistant clinical strains in vitro and in vivo models. P. aeruginosa, S. aureus, and A. baumannii were isolated from clinical infections. Their antibiotic resistance and minimum inhibitory concentration were assessed. LL-37 fragment GF-17D3 peptide was selected from available databases. Scolopendin A2 peptide’s 6th amino acid (proline) was substituted with lysine and peptides and MICs were determined. The biofilm inhibitory activity was quantified at sub MIC concentrations. Synergetic effects of Scolopendin A2 and imipenem were assessed by checkerboard. After mice nasal infection with P. aeruginosa, peptides LD50 was determined. Isolates harbored complete resistance toward the majority of antibiotics and MIC values ranged between 1 and > 512 µg/ml. The majority of isolates exhibited strong biofilm activity. Synthetic peptides showed lower MIC values than antibiotic agents and the lowest MIC values were obtained for synthetic peptides in combination with antibiotics. The Synergisms effect of Scolopendin A2 with imipenem was also determined. Scolopendin A2 was found to have antibacterial efficacy against P. aeruginosa, S. aureus, and A. baumannii with MIC 64 µg/ml, 8 µg/ml, and 16 µg/ml, respectively, and LL37 showed antibacterial efficacy against P. aeruginosa, S. aureus, and A. baumannii with MIC 128 µg/ml, 32 µg/ml, and 32 µg/ml, respectively. Both AMPs decreased biofilms by ≥ 96% at 1 × MIC. The biofilm inhibitory activity was measured at sub MIC concentrations of the peptides and the results demonstrated that Scolopendin A2 exhibited anti-biofilm activity at 1/4 × MIC and 1/2 × MIC concentrations was 47.9 to 63.8%, although LL37 among 1/4 × MIC and 1/2 × MIC concentrations was 21.3 to 49.6% against three pathogens. The combination of Scolopendin A2 and antibiotics demonstrated synergistic activity-resistant strains with FIC values ≤ 0.5 for three pathogens, while LL37 and antibiotics showed synergistic activity FIC values ≤ 0.5 for only P. aeruginosa. Infection model Scolopendin A2 with Imipenem (2 × MIC) was efficacious in vivo, with a 100% survival rate following treatment at 2 × MIC after 120 h. The mRNA expression of biofilm-related genes was decreased for both peptides. Synthesis Scolopendin A2 decreased the expression of biofilm formation genes compared to the control group. Synthetic Scolopendin A2 exhibits antimicrobial activity without causing toxicity on the human epithelial cell line. Based on our findings, it seems that synthetic Scolopendin A2 is an appropriate antimicrobial source. That could be a promising option in combination with antibiotics for a topical medication and in the prevention of acute and chronic infections caused by multidrug-resistant bacteria. Nevertheless, additional experiments are required to assess another potential of this novel AMP.

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Data Availability

Availability of data and materials the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank from Loghman Hakim Hospital for generously providing the clinical samples.

Funding

This work was supported by Pasteur Institute of Iran (PII) grants No. 1936 and No. 66001900.

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Authors and Affiliations

  1. Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran

    Nastaran Farzi, Mana Oloomi & Saeid Bouzari

  2. Department of Hepatitis and AIDS and Blood Borne Diseases, Pasteur Institute of Iran, Tehran, Iran

    Golnaz Bahramali & Saeid Bouzari

  3. Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran

    Seyed Davar Siadat & Saeid Bouzari

  4. Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran

    Seyed Davar Siadat & Saeid Bouzari

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  1. Nastaran Farzi
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Contributions

NF: conceptualization, investigation, methodology, visualization, writing the manuscript, editing, analyzing the data and preparing the figures and tables, data collection from databases, designing the research, performed experiments. MO: developing and optimizing the model, editing, and validation. GB: data collection from databases, editing. SB and SDS: conceptualization, funding acquisition, methodology, project administration, supervision, validation, and designing the research. All authors approved the final version of the manuscript.

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Correspondence to Seyed Davar Siadat or Saeid Bouzari.

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This study contained animal experiments. The ethical approval codes for this study were IR.PII.REC.1400.024 and IR.PII.AEC.1401.004.

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Farzi, N., Oloomi, M., Bahramali, G. et al. Antibacterial Properties and Efficacy of LL-37 Fragment GF-17D3 and Scolopendin A2 Peptides Against Resistant Clinical Strains of Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii In Vitro and In Vivo Model Studies. Probiotics & Antimicro. Prot. (2023). https://doi.org/10.1007/s12602-023-10070-w

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