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A recombinant fungal defensin-like peptide-P2 combats multidrug-resistant Staphylococcus aureus and biofilms

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Abstract

There is an urgent need to discover new active drugs to combat methicillin-resistant Staphylococcus aureus, which is a serious threat to humans and animals and incompletely eliminated by antibiotics due to its intracellular accumulation in host cells, production of biofilms, and persisters. Fungal defensin-like peptides (DLPs) are emerging as a potential source of new antibacterial drugs due to their potent antibacterial activity. In this study, nine novel fungal DLPs were firstly identified by querying against UniProt databases and expressed in Pichia pastoris, and their antibacterial and anti-biofilm ability were tested against multidrug-resistant (MDR) S. aureus. Results showed that among them, P2, the highest activity and expression level, showed low toxicity, no resistance, and high stability. Minimal inhibitory concentrations (MICs) of P2 against Gram-positive bacteria were < 2 μg/mL. P2 exhibited the potent activity against intracellular MDR S. aureus (bacterial reduction in 80–97%) in RAW264.7 macrophages. P2 bound to/disrupted bacterial DNA, wrinkled outer membranes and permeabilized cytoplasmic membranes, but maintained the integrity of bacterial cells. P2 inhibited/eradicated the biofilm and killed 99% persister bacteria, which were resistant to 100× MIC vancomycin. P2 upregulated the anti-inflammatory cytokine (IL-10) and downregulated pro-inflammatory cytokines (TNF-α/IL-1β) and chemokine (MCP-1) levels in RAW 264.7 macrophages and in mice, respectively. Five milligram per kilogram P2 enhanced the survival of S. aureus-infected mice (100%), superior to vancomycin (30 mg/kg), inhibited the bacterial translocation, and alleviated multiple-organ injuries (liver, spleen, kidney, and lung). These data suggest that P2 may be a candidate for novel antimicrobial agents against MDR staphylococcal infections.

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Funding

This study was supported by the National Natural Science Foundation of China (Grants 31672456, 31572444, 31572445, and 31372346), the Project of the National Support Program for Science and Technology in China (Grant 2013BAD10B02), the AMP Direction of the National Innovation Program of Agricultural Science and Technology in CAAS (Grant CAAS-ASTIP-2013-FRI-02), and its Key Project of Alternatives to Antibiotics for Feed Usages (Grant CAAS-ZDXT2018008).

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  1. Na Yang and Ruoyu Mao contributed equally to this work.

Authors and Affiliations

  1. Team of Alternatives to Antibiotics, Gene Engineering Laboratory, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, People’s Republic of China

    Na Yang, Da Teng, Ruoyu Mao, Ya Hao, Xiao Wang, Zhenlong Wang, Xiumin Wang & Jianhua Wang

  2. Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, 100081, People’s Republic of China

    Na Yang, Da Teng, Ruoyu Mao, Ya Hao, Xiao Wang, Zhenlong Wang, Xiumin Wang & Jianhua Wang

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  1. Na Yang
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  2. Da Teng
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Contributions

Na Yang, Xiumin Wang, Ruoyu Mao, Da Teng, and Jianhua Wang conceived and designed experiments. Na Yang carried out all the experiments. Na Yang, Xiumin Wang, and Jianhua Wang contributed in writing. Jianhua Wang contributed in funding acquisition. Ya Hao and Xiao Wang contributed to materials and reagents. Zhenlong Wang contributed in modifying figure.

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Correspondence to Xiumin Wang or Jianhua Wang.

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The mouse experiment was performed according to the Animal Care and Use Committee of the Feed Research Institute of Chinese Academy of Agricultural Sciences (CAAS) and approved by the Laboratory Animal Ethical Committee and its Inspection of the Feed Research Institute of CAAS (AEC-CAAS-20090609).

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Yang, N., Teng, D., Mao, R. et al. A recombinant fungal defensin-like peptide-P2 combats multidrug-resistant Staphylococcus aureus and biofilms. Appl Microbiol Biotechnol 103, 5193–5213 (2019). https://doi.org/10.1007/s00253-019-09785-0

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