Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1–14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.
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Cover Image
Cover Image
The crystal structure of Escherichia coli acetohydroxyacid synthase (AHAS) I holoenzyme, revealing the association between the regulatory subunit (RSU) and catalytic subunit (CSU) in an A2B2 mode. RSU accelerates the open rate of the activation loop of CSU and thus activates the CSU. For more information, see the article by Zhang and colleagues in this issue (pp. 2439–2449). The image was provided by Yuequan Shen.
Selective inhibition of Rhizopus eumelanin biosynthesis by novel natural product scaffold-based designs caused significant inhibition of fungal pathogenesis
Sameh S. M. Soliman, Rania Hamdy, Samia A. Elseginy, Teclegiorgis Gebremariam, Alshaimaa M. Hamoda, Mohamed Madkour, Thenmozhi Venkatachalam, Mai N. Ershaid, Mohammad G. Mohammad, Georgios Chamilos, Ashraf S. Ibrahim; Selective inhibition of Rhizopus eumelanin biosynthesis by novel natural product scaffold-based designs caused significant inhibition of fungal pathogenesis. Biochem J 17 July 2020; 477 (13): 2489–2507. doi: https://doi.org/10.1042/BCJ20200310
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