Data_Sheet_1_Microbial Enzymatic Synthesis of Amikacin Analogs With Antibacterial Activity Against Multidrug-Resistant Pathogens.docx

With the constant emergence of multidrug-resistant gram-negative bacteria, interest in the development of new aminoglycoside (AG) antibiotics for clinical use has increased. The regioselective modification of AG scaffolds could be an efficient approach for the development of new antibiotics with improved therapeutic potency. We enzymatically synthesized three amikacin analogs containing structural modifications in the amino groups and evaluated their antibacterial activity and cytotoxicity. Among them, 6′-N-acyl-3″-N-methylated analogs showed improved antibacterial activity against the multidrug-resistant gram-negative bacteria tested, while exhibiting reduced in vitro nephrotoxicity compared to amikacin. This study demonstrated that the modifications of the 6′-amino group as well as the 3″-amino group have noteworthy advantages for circumventing the AG-resistance mechanism. The regiospecific enzymatic modification could be exploited to develop novel antibacterial agents with improved pharmacological potential.

随着多重耐药革兰氏阴性菌的持续涌现，开发临床应用新型氨基糖苷类（aminoglycoside，AG）抗生素的研究兴趣日益高涨。对氨基糖苷类母核进行区域选择性修饰，不失为开发治疗活性更优的新型抗生素的高效路径。本研究通过酶促合成了三种氨基基团带有结构修饰的阿米卡星类似物，并对其抗菌活性与细胞毒性开展了评估。其中，6'-N-酰基-3''-N-甲基化类似物对本次测试的多重耐药革兰氏阴性菌展现出更优异的抗菌活性，且相较于阿米卡星，其体外（in vitro）肾毒性显著降低。本研究证实，对6'-氨基基团与3''-氨基基团进行修饰，在规避氨基糖苷类耐药机制方面具备显著优势。区域特异性酶促修饰策略，有望用于开发药理学潜力更优的新型抗菌药物。