A novel anti-infection strategy to alleviate antibiotic-resistance problem and non-specific toxicity associated with chemotherapy is explored in this study. It is based on utilizing a bacteriolytic enzyme (lysozyme) as a carrier to allow specific targeting of a potential phenolic antimicrobial drug (triclosan) to microbial cells. Lysozyme (LZ) was complexed, via electrostatic and hydrophobic condensation at alkaline pH, to various degrees with triclosan (TCS), a negatively charged phenolic antimicrobial that inhibits bacterial fatty acid synthesis. Fluorescence and absorbance spectra analysis revealed non-covalent association of TCS with the aromatic residues at the interior of LZ molecule. The conjugation greatly promoted the lytic activity of LZ as the degree of TCS derivatization increased. The complexation with LZ turned TCS into completely soluble in aqueous solution. TCS-LZ complexes showed significantly enhanced bactericidal activity against several strains of Gram-positive and Gram-negative bacteria compared to the activity of TCS or LZ alone when tested at the same molar basis. Strikingly, TCS-LZ complex, but not LZ or TCS alone, exhibited unique specificity to scavenge superoxide radicals, generated by the natural xanthine/xanthine oxidase coupling system, without affecting the catalytic function of oxidase. This finding is the first to describe that the membrane disrupting function of lysozyme can be utilized to specifically target antimicrobial drug(s) to pathogen cells and heralding a fascinating opportunity for the potential candidacy of TCS-LZ as novel antimicrobial strategy for human therapy.

译文

本研究探索了一种新的抗感染策略,以减轻与化疗相关的抗生素耐药性问题和非特异性毒性。它基于利用溶菌酶 (溶菌酶) 作为载体,允许将潜在的酚类抗菌药物 (三氯生) 特异性靶向微生物细胞。溶菌酶 (LZ) 在碱性pH下通过静电和疏水缩合与三氯生 (TCS) 复合,三氯生是一种带负电荷的酚类抗菌剂,可抑制细菌脂肪酸的合成。荧光和吸收光谱分析显示TCS与LZ分子内部的芳族残基非共价缔合。随着TCS衍生化程度的增加,共轭大大提高了LZ的裂解活性。与LZ的络合使TCS完全溶于水溶液。与在相同摩尔基础上测试的TCS或LZ单独的活性相比,TCS-LZ复合物对几种革兰氏阳性和革兰氏阴性细菌的杀菌活性显着增强。令人惊讶的是,TCS-LZ复合物 (而不是LZ或TCS) 表现出独特的特异性,可清除由天然黄嘌呤/黄嘌呤氧化酶偶联系统产生的超氧化物自由基,而不会影响氧化酶的催化功能。这一发现是第一个描述溶菌酶的膜破坏功能可用于特异性靶向病原体细胞的抗菌药物,并预示着tcs-lz作为人类治疗新型抗菌策略的潜在候选资格的迷人机会。

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