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Potent effects of amino acid scanned antimicrobial peptide Feleucin-K3 analogs against both multidrug-resistant strains and biofilms of Pseudomonas aeruginosa

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Abstract

Pseudomonas aeruginosa is particularly difficult to treat because it possesses a variety of resistance mechanisms and because it often forms biofilms. Antimicrobial peptides represent promising candidates for future templates of antibiotic-resistant bacterial infections due to their unique mechanism of antimicrobial action. In this study, we first found that the antimicrobial peptide Feleucin-K3 has potent antimicrobial activity against not only the standard strain of P. aeruginosa but also against the multidrug-resistant strains isolated from clinics. Then, the structure–activity relationship of the peptide was investigated using alanine and d-amino acid scanning. Among the analogs synthesized, FK-1D showed much more potent antimicrobial activity, superior stability, and very low toxicity, and it was able to permeabilize bacterial membranes. Furthermore, it exhibited significant anti-biofilm activity. More importantly, FK-1D showed excellent antimicrobial activity in vivo, especially against clinical multidrug-resistant bacteria, in contrast to ceftazidime. Our results suggested that FK-1D could be subjected to fixed-point modification in the first and fourth sites to further optimize its medicinal properties and potential as a lead compound for the treatment of infections caused by multidrug-resistant P. aeruginosa and the associated biofilms.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81602945, 81673283, and 81473095), the Program for Ministry of Education “Peptide Drugs” Innovation Team (IRT_15R27), the China Postdoctoral Science Foundation (2016M592593), and the Fundamental Research Funds for the Central Universities (lzujbky-2017-k11, lzujbky-2017-119, and lzujbky-2017-139).

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Junqiu Xie & Xianxing Jiang

  2. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China

    Junqiu Xie, Yao Li, Jing Li, Zhibin Yan, Dan Wang, Xiaomin Guo, Jianfeng Zhang, Bangzhi Zhang, Lingyun Mou & Wenle Yang

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  1. Junqiu Xie
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Correspondence to Xianxing Jiang.

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This article does not contain any studies with human participants performed by any other authors. All experiments involving animals were performed in strict compliance with the directions of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The official procedure was approved by the Ethics Committee of Lanzhou University (Permit Number: SYXK Gan 2013-0003), China.

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Xie, J., Li, Y., Li, J. et al. Potent effects of amino acid scanned antimicrobial peptide Feleucin-K3 analogs against both multidrug-resistant strains and biofilms of Pseudomonas aeruginosa. Amino Acids 50, 1471–1483 (2018). https://doi.org/10.1007/s00726-018-2625-4

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