Affiliation:
1. Faculty of Pharmacy, University of Science and Technology, Omdurman, Sudan
2. Department of Chemistry, Ahmadu Bello University, Zaria, Nigeria
3. Institute of Organic Chemistry, University of Würzburg, Würzburg, Germany
4. Faculty of Sciences, University of Kinshasa, Kinshasa, Democratic Republic of the Congo
Abstract
ABSTRACT
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 (IC
50
=
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.
Publisher
American Society for Microbiology
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