A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi

被引：40

作者：

dos Reis, Thaila Fernanda ^{[1
]}

de Castro, Patricia Alves ^{[1
]}

Bastos, Rafael Wesley ^{[1
]}

Pinzan, Camila Figueiredo ^{[1
]}

Souza, Pedro F. N. ^{[2
]}

Ackloo, Suzanne ^{[3
]}

Hossain, Mohammad Anwar ^{[4
]}

Drewry, David Harold ^{[4
,5
]}

Alkhazraji, Sondus ^{[6
]}

Ibrahim, Ashraf S. ^{[6
,7
]}

Jo, Hyunil ^{[8
]}

Lightfoot, Jorge D. ^{[9
]}

Adams, Emily M. ^{[9
]}

Fuller, Kevin K. ^{[9
,10
]}

deGrado, William F. ^{[8
]}

Goldman, Gustavo H. ^{[1
]}

机构：

[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Ribeirao Preto, Brazil

[2] Univ Fed Ceara, Drug Res & Dev Ctr, Dept Physiol & Pharmacol, BR-60451 Fortaleza, CE, Brazil

[3] Univ Toronto, Struct Genom Consortium, 101 Coll St,MaRS South Tower,Suite 700, Toronto, ON M5G 1L7, Canada

[4] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 USA

[5] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Sch Med, Dept Med, Chapel Hill, NC 27599 USA

[6] Univ Calif Los Angeles UCLA, Lundquist Inst Biomed Innovat Harbor, Div Infect Dis, Med Ctr, Torrance, CA 90502 USA

[7] David Geffen Sch Med UCLA, Los Angeles, CA 90095 USA

[8] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA

[9] Univ Oklahoma Hlth Sci Ctr, Dept Ophthalmol, Oklahoma City, OK 73104 USA

[10] Univ Oklahoma Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

巴西圣保罗研究基金会; 美国国家卫生研究院;

关键词：

SHOCK-PROTEIN; 90; DE-NOVO DESIGN; PULMONARY ASPERGILLOSIS; ANTIMICROBIAL POLYMERS; SYNTHETIC MIMICS; DRUG-RESISTANCE; DIAGNOSIS; CALCINEURIN; INHIBITORS; STRATEGIES;

D O I：

10.1038/s41467-023-37573-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Current treatment of fungal infections is threatened by emerging antifungal drug resistance. In this work, the authors explore the synergistic activity of a host defense peptide mimetic, brilacidin, with caspofungin against a panel of fungal strains. Fungal infections cause more than 1.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening fungal diseases. Here, we identify the host defense peptide mimetic, brilacidin (BRI) as a synergizer with caspofungin (CAS) against CAS-sensitive and CAS-resistant isolates of Aspergillus fumigatus, Candida albicans, C. auris, and CAS-intrinsically resistant Cryptococcus neoformans. BRI also potentiates azoles against A. fumigatus and several Mucorales fungi. BRI acts in A. fumigatus by affecting cell wall integrity pathway and cell membrane potential. BRI combined with CAS significantly clears A. fumigatus lung infection in an immunosuppressed murine model of invasive pulmonary aspergillosis. BRI alone also decreases A. fumigatus fungal burden and ablates disease development in a murine model of fungal keratitis. Our results indicate that combinations of BRI and antifungal drugs in clinical use are likely to improve the treatment outcome of aspergillosis and other fungal infections.

引用

页数：19

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