New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box<sup>®</sup> that present synergism with itraconazole

Coelho, Rowena Alves; Alves, Gabriela Machado; Figueiredo-Carvalho, Maria Helena Galdino; Almeida-Silva, Fernando; de Souza, Gabriela Rodrigues; Lourenço, Maria Cristina da Silva; Brito-Santos, Fábio; Amaral, Ana Claudia Fernandes; Almeida-Paes, Rodrigo

doi:10.1590/0074-02760220089

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RESEARCH ARTICLE • Mem. Inst. Oswaldo Cruz 117 • 2022 • https://doi.org/10.1590/0074-02760220089 linkcopy

New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box^® that present synergism with itraconazole

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

BACKGROUND Black fungi of the Herpotrichiellaceae family are agents of chromoblastomycosis and phaeohyphomycosis. There are few therapeutic options for these infections and it is common to associate antifungal drugs in their treatment.

OBJECTIVES To investigate the Medicines for Malaria Venture (MMV) Pathogen Box^® for possible compounds presenting synergism with antifungal drugs used to treat black fungal infections.

METHODS An initial screening of the Pathogen Box^® compounds was performed in combination with itraconazole or terbinafine at sub-inhibitory concentrations against Fonsecaea pedrosoi. Hits were further tested against eight Herpotrichiellaceae using the checkerboard method.

FINDINGS No synergism was observed with terbinafine. MMV687273 (SQ109) and MMV688415 showed synergism with itraconazole against F. pedrosoi. Synergism of these compounds was confirmed with some black fungi by the checkerboard method. SQ109 and itraconazole presented synergism for Exophiala dermatitidis, F. pedrosoi, F. monophora and F. nubica, with fungicidal activity for F. pedrosoi and F. monophora. MMV688415 presented synergism with itraconazole only for F. pedrosoi, with fungicidal activity. The synergic compounds had high selectivity index values when combined with itraconazole.

MAIN CONCLUSIONS These compounds in combination, particularly SQ109, are promising candidates to treat Fonsecaea spp. and E. dermatitidis infections, which account for most cases of chromoblastomycosis and phaeohyphomycosis.

Key words:
Exophiala; Fonsecaea; synergism; drug repurposing; itraconazole; Pathogen Box

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[TFN1] ^*Bold FICI values indicate synergistic interactions. MIC: minimum inhibitory concentration.

Strains	MIC (µM)			FICI SQ109/ITZ	MIC (µM)			FICI 688415/ITZ
Strains	SQ109	ITZ	SQ109/ITZ	FICI SQ109/ITZ	688415	ITZ	688415/ITZ	FICI 688415/ITZ
Cladophialophora carrionii	2.0	0.25	1.0/0.125	1	≥ 32	0.25	0,25/0,25	1.007
Phialophora verrucosa	4.0	1.0	0.015/4.0	1.015	≥ 32	1.0	1.0/0.5	0.56
Exophiala dermatitidis	4.0	1.0	0.5/0.125	0.25*	≥ 32	1.0	0.25/1.0	1.01
Exophiala heteromorpha	16	0.50	16/0.015	1.03	≥ 32	0.50	0.25/0.50	1.01
Fonsecaea pedrosoi	4.0	0.50	0.50/0.0625	0.25	≥ 32	0.50	2.0/0.125	0.37
Fonsecaea monophora	4.0	0.50	0.25/0.125	0.31	≥ 32	0.25	0.25/0.25	1.01
Fonsecaea nubica	4.0	0.25	1.0/0.0625	0.50	≥ 32	0.50	0.25/0.50	1.01
Rhinocladiella similis	8.0	0.50	4.0/0.125	0.75	≥ 32	0.50	0.25/0.50	1.01

Strains	MIC (µM)			FICI SQ109/ITZ
Strains	SQ109	ITZ	SQ109/ITZ	FICI SQ109/ITZ
34242 Fonsecaea nubica	4.0	0.50	1.0/0.125	0.50*
34904 Fonsecaea monophora	4.0	0.25	1.0/0.125	0.75
36134 Fonsecaea monophora	4.0	0.25	1.0/0.03125	0.37
36831 Fonsecaea monophora	4.0	0.25	1.0/0.125	0.75
38714 Fonsecaea pedrosoi	4.0	0.25	1.0/0.0625	0.50
41080 Fonsecaea monophora	4.0	0.25	1.0/0.0625	0.50

Strains	MFC (µM)			FFCI SQ109/ITZ	MFC (µM)			FFCI 688415/ITZ
Strains	SQ109	ITZ	SQ109/ITZ	FFCI SQ109/ITZ	688415	ITZ	688415/ITZ	FFCI 688415/ITZ
Cladophialophora carrionii	2.0	1.0	1.0/0.125	0.62	≥ 32	2.0	8.0/1.0	0.75
Phialophora verrucosa	8.0	4.0	16/4.0	3	≥ 32	1.0	1.0/2.0	2.015
Exophiala heteromorpha	16	8.0	16/0.125	1.015	≥ 32	8.0	16/1.0	0.62
Exophiala jeanselmei	≥32	8.0	16/4.0	1	≥ 32	8.0	0.25/4.0	0.507
Fonsecaea pedrosoi	4.0	2.0	0.0625/0.50	0.26*	≥ 32	2.0	2.0/0.125	0.25
Fonsecaea monophora	4.0	2.0	0.25/0.125	0.12	≥ 32	2.0	4.0/2.0	1.125
Fonsecaea nubica	16	2.0	1.0/2.0	1.062	≥ 32	4.0	16/1.0	0.75
Rhinocladiella similis	8.0	8.0	4.0/8.0	1.50	≥ 32	4.0	16/2.0	1

Strains	MMV687273 (SQ109)		MMV688415
Strains	SI alone	SI after combination	SI alone	SI after combination
Cladophialophora carrionii	50	100	1.2	153.6
Phialophora verrucosa	25	6666.66	1.2	38.4
Exophiala heteromorpha	25	200	1.2	153.6
Exophiala jeanselmei	6.25	6.25	1.2	153.6
Fonsecaea pedrosoi	25	200	1.2	19.2
Fonsecaea monophora	25	400	1.2	153.6
Fonsecaea nubica	25	100	1.2	153.6
Rhinocladiella similis	12.50	25	1.2	153.6

New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box® that present synergism with itraconazole

Abstract

New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box^® that present synergism with itraconazole