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BamA-targeted antimicrobial peptide design for enhanced efficacy and reduced toxicity

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Abstract

The emergence of drug-resistant superbugs has necessitated a pressing need for innovative antibiotics. Antimicrobial peptides (AMPs) have demonstrated broad-spectrum antibacterial activity, reduced susceptibility to resistance, and immunomodulatory effects, rendering them promising for combating drug-resistant microorganisms. This study employed computational simulation methods to screen and design AMPs specifically targeting ESKAPE pathogens. Particularly, AMPs were rationally designed to target the BamA and obtain novel antimicrobial peptide sequences. The designed AMPs were assessed for their antibacterial activities, mechanisms, and stability. Molecular docking and dynamics simulations demonstrated the interaction of both designed AMPs, 11pep and D-11pep, with the β1, β9, β15, and β16 chains of BamA, resulting in misfolding of outer membrane proteins and antibacterial effects. Subsequent antibacterial investigations confirmed the broad-spectrum activity of both 11pep and D-11pep, with D-11pep demonstrating higher potency against resistant Gram-negative bacteria. D-11pep exhibited MICs of 16, 8, and 32 μg/mL against carbapenem-resistant Escherichia coli, carbapenem-resistant Pseudomonas aeruginosa, and multi-drug-resistant Acinetobacter baumannii, respectively, with a concomitant lower resistance induction. Mechanism of action studies confirmed that peptides could disrupt the bacterial outer membrane, aligning with the findings of molecular dynamics simulations. Additionally, D-11pep demonstrated superior stability and reduced toxicity in comparison to 11pep. The findings of this study underscore the efficacy of rational AMP design that targets BamA, along with the utilization of D-amino acid replacements as a strategy for developing AMPs against drug-resistant bacteria.

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Data Availability Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request. Additionally, a portion of the data supporting this study is publicly available through the following sources: APD3 (https://aps.unmc.edu), PDB (https://www.rcsb.org/), and EMSFold (https://esmatlas.com/).

Abbreviations

CRE:

Carbapenem-resistant Escherichia coli

MRSA:

Methicillin-resistant Staphylococcus aureus

CRPA:

Carbapenem-resistant Pseudomonas aeruginosa

MDRAB:

Multi-drug-resistant Acinetobacter baumannii

AMPs:

Antimicrobial peptides

MIC:

Minimum Inhibitory Concentration

MHB:

Mueller–Hinton Broth

LB:

Luria–Bertani Broth

MBC:

Minimum Bactericidal Concentration

SEM:

Scanning Electron Microscopy

FBS:

Fetal Bovine Serum

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Funding

This study was supported by the Natural Science Foundation of Chongqing (CSTB2022NSCQ-MSX1327), the Innovation Project of Chongqing Stay and Create Program (cx2020012), the Graduate Education Research Fund of Chongqing Municipal Education Commission, and the Graduate Innovation Project of Chongqing University of Technology (gzlcx20223347).

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Authors and Affiliations

  1. Pharmacy and Bioengineering of Technology, Chongqing University of Technology, Chongqing, 400054, China

    Li Yang, Minghe Luo, Zhou Liu, Yuepeng Li, Zhihua Lin & Yuanqiang Wang

  2. Chongqing Municipal Key Laboratory of Institutions of Higher Education of Target Based Drug Screening and Activity Evaluation, Chongqing, 400054, China

    Minghe Luo, Zhihua Lin & Yuanqiang Wang

  3. Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing, 400054, China

    Minghe Luo, Zhihua Lin & Yuanqiang Wang

  4. The People’s Hospital of Dazu, Chongqing, 402360, China

    Shan Geng

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  1. Li Yang
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  2. Minghe Luo
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  3. Zhou Liu
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  4. Yuepeng Li
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  6. Shan Geng
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  7. Yuanqiang Wang
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Contributions

YW and LY collaborated on the conception and design of the study, with LY conducting the experiments, analyzing the data, and writing the manuscript. ML and SG offered insights into data interpretation and critically revised the manuscript. ZL, YL and ZL provided valuable technical guidance throughout the study. All authors reviewed the manuscript.

Corresponding author

Correspondence to Yuanqiang Wang.

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Conflict of interest

The authors declare no competing financial interest.

Ethical approval

This research project does not involve any human or animal subjects and therefore does not require ethical approval. The study will be conducted using only publicly available data or secondary data analysis. As such, it does not pose any risks or harm to individuals, and the privacy and confidentiality of any data analyzed will be protected. We are committed to conducting this study in accordance with the highest ethical standards and will adhere to all relevant laws and regulations.

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Handling editor: J. Gonzalez-Lopez.

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Yang, L., Luo, M., Liu, Z. et al. BamA-targeted antimicrobial peptide design for enhanced efficacy and reduced toxicity. Amino Acids 55, 1317–1331 (2023). https://doi.org/10.1007/s00726-023-03307-z

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