Antimicrobial peptides (AMPs) constitute a promising alternative for the development of new antibiotics that could potentially counteract the growing number of antibiotic-resistant bacteria. However, the AMP structure⁻function relationships remain unclear and detailed studies are still necessary. The positively charged amino acid residues (Arg and Lys) play a crucial role in the activity of most AMPs due to the promotion of electrostatic interactions between the peptides and bacterial membranes. In this work we have analyzed the antimicrobial and structural properties of several Trp-rich AMPs containing exclusively either Arg or Lys as the positively charged residues. Their antimicrobial activity and mechanism of action were investigated, showing that Lys residues give rise to a reduced antimicrobial potency for most peptides, which was correlated, in turn, with a decrease in their ability to permeabilize the cytoplasmic membrane of Escherichia coli. Additionally, the presence of Arg and Lys renders the peptides susceptible to degradation by proteases, such as trypsin, limiting their therapeutic use. Therefore, modifications of the side chain length of Arg and Lys were investigated in an attempt to improve the protease resistance of AMPs. This approach resulted in enhanced stability to trypsin digestion, and in several cases, shorter sidechains conserved or even improved the antimicrobial activity. All together, these results suggest that Arg-to-Lys substitutions, coupled with side chain length modifications, can be extremely useful for improving the activity and stability of AMPs.

中文翻译：

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通过Arg / Lys取代提高Trp丰富的抗菌肽的活性，并改变阳离子残基的长度。

抗菌肽（AMP）构成了开发新抗生素的有前途的替代品，这些新抗生素可能会抵消不断增加的抗药性细菌的数量。但是，AMP结构与功能的关系尚不清楚，仍需进一步研究。带正电的氨基酸残基（Arg和Lys）在大多数AMPs的活性中起着至关重要的作用，因为它们促进了肽与细菌膜之间的静电相互作用。在这项工作中，我们分析了几种仅含有Arg或Lys作为带正电残基的富含Trp的AMPs的抗菌和结构特性。对它们的抗菌活性和作用机理进行了研究，结果表明，Lys残基使大多数肽的抗菌效力降低，这是相关的，继而，它们透化大肠杆菌细胞质膜的能力降低。另外，Arg和Lys的存在使肽易于被诸如胰蛋白酶的蛋白酶降解，从而限制了它们的治疗用途。因此，研究了Arg和Lys的侧链长度的修饰，以试图改善AMPs的蛋白酶抗性。这种方法提高了对胰蛋白酶消化的稳定性，并且在某些情况下，较短的侧链可以保留甚至改善抗菌活性。总之，这些结果表明，Arg-to-Lys取代以及侧链长度的修饰对于提高AMP的活性和稳定性非常有用。另外，Arg和Lys的存在使肽易于被诸如胰蛋白酶的蛋白酶降解，从而限制了它们的治疗用途。因此，研究了Arg和Lys的侧链长度的修饰，以试图改善AMPs的蛋白酶抗性。这种方法提高了对胰蛋白酶消化的稳定性，并且在某些情况下，较短的侧链可以保留甚至改善抗菌活性。总之，这些结果表明，Arg-to-Lys取代以及侧链长度的修饰对于提高AMP的活性和稳定性非常有用。另外，Arg和Lys的存在使肽易于被诸如胰蛋白酶的蛋白酶降解，从而限制了它们的治疗用途。因此，研究了Arg和Lys的侧链长度的修饰，以试图改善AMPs的蛋白酶抗性。这种方法提高了对胰蛋白酶消化的稳定性，并且在某些情况下，较短的侧链可以保留甚至改善抗菌活性。总之，这些结果表明，Arg-to-Lys取代以及侧链长度的修饰对于提高AMP的活性和稳定性非常有用。为了改善AMPs的蛋白酶抗性，研究了Arg和Lys的侧链长度的修饰。这种方法提高了对胰蛋白酶消化的稳定性，并且在某些情况下，较短的侧链可以保留甚至改善抗菌活性。总之，这些结果表明，Arg-to-Lys取代以及侧链长度的修饰对于提高AMP的活性和稳定性非常有用。为了改善AMPs的蛋白酶抗性，研究了Arg和Lys的侧链长度的修饰。这种方法提高了对胰蛋白酶消化的稳定性，并且在某些情况下，较短的侧链可以保留甚至改善抗菌活性。总之，这些结果表明，Arg-to-Lys取代以及侧链长度的修饰对于提高AMP的活性和稳定性非常有用。