College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, Guangdong, China.
Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou 510642, Guangdong, China.
ACS Nano. 2024 Nov 12;18(45):31435-31450. doi: 10.1021/acsnano.4c11443. Epub 2024 Oct 30.
Lasso peptides, natural biological microcins composed of small molecules, have demonstrated efficient bactericidal activity. However, a single lasso peptide is characterized by a narrow and targeted bactericidal spectrum. In this study, a chitosan (CN) derivative-based polymer nanomaterial incorporating three lasso peptides (MccY, MccJ25, and Klebsidin) was designed and synthesized to broaden its antimicrobial spectrum. To enhance resistance to acid and alkali conditions, arginine was appended to the terminus of conjugates, resulting in Chitosan-Lasso-Peptides-Arg (CN-LPs-Arg), and the nanomaterial biocompatibility and bactericidal activity were characterized. Chemical stability test results demonstrate that CN-LPs-Arg effectively buffered the acid-base effect of the compound. Notably, CN-LPs-Arg extended the antimicrobial spectrum of Gram-negative and Gram-positive strains including , , and (MIC = 0.01-1.0 μM). CN-LPs-Arg exerts its destructive effects on bacteria via a series of mechanisms; it adheres to and then penetrates the membrane, causes rupture, and leads to bacterial death. Transcriptomic data revealed that CN-LPs-Arg produced a distinct inhibitory effect on ribosomal protein subunits synthesis pathways and membrane metabolic inhibition. Furthermore, CN-LPs-Arg was nontoxic to cells and exhibited excellent biocompatibility. CN-LPs-Arg reduced bacterial burden in organs and the levels of inflammatory factors IL-6, IL-8, and TNF-α in tissues of mice with acute bacterial infections. Furthermore, it promoted the recovery of -infected C57BL/6 mice, demonstrating a favorable therapeutic effect in vivo. The multilasso peptide-based synergistic nanocomposite of CN-LPs-Arg exhibited high stability as a broad-spectrum antimicrobial agent with potential for combined antibacterial therapy and utilization in the fields of food, biomedicine, and public health.
微菌素是由小分子组成的天然生物类小菌素，具有高效的杀菌活性。然而，单一的微菌素具有狭窄且靶向的杀菌谱。在这项研究中，设计并合成了一种基于壳聚糖（CN）衍生物的聚合物纳米材料，该纳米材料包含三种微菌素（MccY、MccJ25 和 Klebsidin），以拓宽其抗菌谱。为了增强对酸碱性条件的抵抗力，在缀合物的末端添加了精氨酸，得到壳聚糖-微菌素-精氨酸（CN-LPs-Arg），并对纳米材料的生物相容性和杀菌活性进行了表征。化学稳定性测试结果表明，CN-LPs-Arg 有效地缓冲了化合物的酸碱效应。值得注意的是，CN-LPs-Arg 扩展了革兰氏阴性和革兰氏阳性菌株的抗菌谱，包括 、 、 和 （MIC = 0.01-1.0 μM）。CN-LPs-Arg 通过一系列机制对细菌发挥破坏作用；它首先附着在细胞膜上，然后穿透细胞膜，导致破裂，从而导致细菌死亡。转录组数据显示，CN-LPs-Arg 对核糖体蛋白亚基合成途径和膜代谢抑制产生了明显的抑制作用。此外，CN-LPs-Arg 对细胞无毒，具有良好的生物相容性。CN-LPs-Arg 降低了急性细菌感染小鼠器官中的细菌负荷和组织中炎症因子 IL-6、IL-8 和 TNF-α 的水平。此外，它促进了感染的 C57BL/6 小鼠的恢复，在体内显示出良好的治疗效果。基于多微菌素的协同纳米复合材料的 CN-LPs-Arg 作为一种广谱抗菌剂具有很高的稳定性，具有联合抗菌治疗的潜力，并可应用于食品、生物医学和公共卫生领域。
