Mycetoma是皮下组织的破坏性被忽视的热带感染。它是由真菌和细菌病原体引起的,被认为是细菌瘤和放线菌瘤,分别。Mycetoma治疗涉及诊断致病微生物作为开出适当药物的先决条件。真菌性真菌瘤病原体的当前治疗,比如Madurellamycetomatis,包括长期使用伊曲康唑抗真菌药物,然后进行手术,然而,临床结果通常不令人满意。放线菌瘤,相反,通常对复方新诺明和阿米卡星治疗有反应。因此,迫切需要发现新型广谱抗微生物剂以避免耗时且昂贵的诊断。使用刃天青测定,对一系列23种萘啶异喹啉(NIQ)生物碱和相关的萘醌进行了体外筛选,以对抗两种真菌菌株M.cycetomatis和三种细菌菌株Actinomaduramadurae和A.syzygii。七个NIQs,主要是二聚体,对至少一种引起霉菌瘤的病原体的菌株显示出有希望的体外活性,萘醌没有任何活性。合成的NIQ二聚体,8,8\'\'\'-O,O-二甲基胶束胺A(18),抑制所有测试的真菌和细菌菌株(IC50=2.81-12.07µg/mL)。其中一个二聚体NIQs,胶束胺B(14),抑制M.mycetomatis的菌株,并显着提高了感染M.mycetomatis浓度为1和4µg/mL的Galleriamelonella幼虫的存活率,对未感染的幼虫没有毒性.因此,具有抗菌活性的广谱二聚体NIQs,如14和18,被认为是值得进一步优化的化合物,以开发新型的抗微生物药物。
Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and
actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as Madurella mycetomatis, consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes.
Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to in vitro screening against two fungal strains of M. mycetomatis and three bacterial strains of Actinomadura madurae and A. syzygii. Seven NIQs, mostly dimers, showed promising in vitro activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8\'\'\'-O,O-dimethylmichellamine A (18), inhibited all tested fungal and bacterial strains (IC50 = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (14), inhibited a strain of M. mycetomatis and significantly enhanced the survival rate of Galleria mellonella larvae infected with M. mycetomatis at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like 14 and 18 with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.