2. Academic Validation
  3. Polymyxin B-inspired non-hemolytic tyrocidine A analogues with significantly enhanced activity against gram-negative bacteria: How cationicity impacts cell specificity and antibacterial mechanism

Polymyxin B-inspired non-hemolytic tyrocidine A analogues with significantly enhanced activity against gram-negative bacteria: How cationicity impacts cell specificity and antibacterial mechanism

  • Eur J Med Chem. 2021 Oct 5:221:113488. doi: 10.1016/j.ejmech.2021.113488.
Jibao Zhu 1,  Chengfei Hu 1,  Zizhen Zeng 1,  Xiaoyu Deng 2,  Lingbing Zeng 3,  Saisai Xie 1,  Yuanying Fang 1,  Yi Jin 1,  Valérie Alezra 4,  Yang Wan 5
Affiliations

Affiliations

  • 1 National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, PR China.
  • 2 Minist Educ, Key Lab Modern Preparat TCM, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, PR China.
  • 3 Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu, Nanchang, 330006, PR China.
  • 4 Laboratoire de Méthodologie, Synthèse et Molécules Thérapeutiques (ICMMO), UMR 8182, CNRS, Université Paris-Saclay, Bât 410, Facultédes Sciences D'Orsay, Orsay, 291405, France.
  • 5 National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, PR China; Laboratoire de Méthodologie, Synthèse et Molécules Thérapeutiques (ICMMO), UMR 8182, CNRS, Université Paris-Saclay, Bât 410, Facultédes Sciences D'Orsay, Orsay, 291405, France; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, 15 Yuchai Road, Guilin, 541004, PR China. Electronic address: [email protected].
PMID: 33991963 DOI: 10.1016/j.ejmech.2021.113488
Abstract

Naturally occurring cyclic antimicrobial peptides (AMPs) such as tyrocidine A (Tyrc A) and gramicidin S (GS) are appealing targets for the development of novel Antibiotics. However, their therapeutic potentials are limited by undesired hemolytic activity and relatively poor activity against Gram-negative bacteria. Inspired by polycationic Lipopeptide polymyxin B (PMB), the so called 'last-resort' Antibiotic for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, we synthesized and biologically evaluated a series of polycationic analogues derived from Tyrc A. We were able to obtain peptide 8 that possesses 5 positive charges exhibiting potent activities against both Gram-negative and Gram-positive bacteria along with totally diminished hemolytic activity. Intriguingly, Antibacterial mechanism studies revealed that, rather than the 'pore forming' model that possessed by Tyrc A, peptide 8 likely diffuses membrane in a 'detergent-like' manner. Furthermore, when treating mice with peritonitis-sepsis, peptide 8 showed excellent Antibacterial and anti-inflammatory activities in vivo.

Keywords

Antimicrobial peptide; Cationicity; Gram-negative bacteria; Hemolysis; Tyrocidine A.

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