Kuppusamy Rajesh, Yasir Muhammad, Berry Thomas, Cranfield Charles G, Nizalapur Shashidhar, Yee Eugene, Kimyon Onder, Taunk Aditi, Ho Kitty K K, Cornell Bruce, Manefield Mike, Willcox Mark, Black David StC, Kumar Naresh
School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
School of Optometry and Vision Science, UNSW Australia, Sydney, NSW 2052, Australia.
Eur J Med Chem. 2018 Jan 1;143:1702-1722. doi: 10.1016/j.ejmech.2017.10.066. Epub 2017 Nov 11.
Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3'-amino-[1,1'-biphenyl]-3-carboxylic acid backbone to mimic the essential properties of natural AMPs. By altering hydrophobicity and charge, we identified the most potent analogue 25g that was active against both Gram-positive Staphylococcus aureus (MIC = 15.6 μM) and Gram-negative Escherichia coli (MIC = 7.8 μM) bacteria. Cytoplasmic permeability assay results revealed that 25g acts primarily by depolarization of lipids in cytoplasmic membranes. The active compounds were also investigated for their cytotoxicity to human cells, lysis of lipid bilayers using tethered bilayer lipid membranes (tBLMs) and their activity against established biofilms of S. aureus and E. coli.
抗菌肽（AMPs）及其合成模拟物作为传统抗生素的新替代品，近来受到了关注，旨在应对许多微生物中抗生素耐药性的上升。抗菌肽是大多数生物体天然防御机制的一部分，它们对细菌也具有独特的作用机制。在此，通过引入3'-氨基-[1,1'-联苯]-3-羧酸主链来模拟天然抗菌肽的基本特性，合成了一系列新的短两亲性阳离子肽模拟物。通过改变疏水性和电荷，我们确定了最有效的类似物25g，它对革兰氏阳性金黄色葡萄球菌（MIC = 15.6 μM）和革兰氏阴性大肠杆菌（MIC = 7.8 μM）均有活性。细胞质通透性测定结果表明，25g主要通过使细胞质膜中的脂质去极化起作用。还研究了活性化合物对人细胞的细胞毒性、使用栓系双层脂质膜（tBLM）对脂质双层的裂解作用以及它们对金黄色葡萄球菌和大肠杆菌成熟生物膜的活性。
