Derivatives of the antimalarial drug mefloquine are broad spectrum antifungal molecules with activity against drug-resistant clinical isolates

Abstract

20 21 22 23The antifungal pharmacopeia is critically small, particularly in light of the recent 24 emergence of multi-drug-resistant pathogens such as Candida auris. Herein, we report 25 that derivatives of the anti-malarial drug mefloquine have broad spectrum antifungal 26 activity against pathogenic yeasts and molds. In addition, the mefloquine derivatives have 27 activity against clinical isolates that are resistant to one or more of the three classes of 28 drugs currently used to treat invasive fungal infections, indicating that they have a novel 29 mechanism of action. Importantly, the in vitro toxicity profiles using human cell lines 30 indicate that the mefloquine derivatives are very similar to the parent mefloquine despite 31 being up to 64-fold more active against fungal cells. In addition to direct antifungal activity, 32 sub-inhibitory concentrations of the mefloquine derivatives inhibit the expression of 33 virulence traits including filamentation in C. albicans and capsule formation/melanization 34 in C. neoformans. Mode/mechanism of action experiments indicate that the mefloquine 35 derivatives interfere with both mitochondrial and vacuolar function as part of a multi-target 36 mechanism of action. The broad-spectrum scope of activity, blood-brain-barrier 37 penetration, and large number of previously synthesized analogs available combine to 38 support the further optimization and development of the antifungal activity of this general 39 class of drug-like molecules. 40 41 was the availability of structural analogs of MEF through the NCI experimental 88 therapeutics program. 89 MEF has also been studied as a repurposing candidate against other human 90 parasites including schistosomiasis, toxoplasmosis, and echinococcosis (11-17). MEF 91 has also shown antibacterial activity against Streptococcus pneumoniae and 92 Mycobacterium tuberculosis (18, 19). Additionally, repurposing efforts have found 93 antiviral activity against Ebola, Dengue, and Zika virus (20, 21). Most importantly a small 94 set of MEF-derivatives were shown to have activity against Cryptococcus neoformans 95 and Candida albicans (22). Despite these promising findings, no additional 96 characterization of the antifungal activity of the MEF-derivatives has been reported. Here, 97 we show that MEF-derivatives have broad spectrum antifungal activity against both 98 susceptible and drug-resistant fungi; show synergy with existing antifungal drugs; 99 modulate the expression of virulence traits in both C. albicans and C. neoformans; and 100interfere with the functions and interactions of mitochondria and vacuoles in fungi. 101 RESULTS 102Mefloquine derivatives have in vitro antifungal activity against a variety of human 103 fungal pathogens. 104 To explore the antifungal activity of the MEF scaffold, we first tested MEF against 105 a set of reference strains of pathogenic fungi including C. albicans, C. glabrata, C. auris, 106 C. neoformans, and A. fumigatus as well as the model yeast S. cerevisiae (Table 1). 107 Consistent with...

Augmenting Azoles with Drug Synergy to Expand The Antifungal Toolbox

“…Chloroquine and artemisin interacted synergistically with azoles against azole-resistant Candida strains, while pyrvinium pamoate-azole synergy was observed in a broad suite of dermatophytes [140][141][142][143]. Mefloquine and related compounds displayed limited synergy in C. neoformans, but did manage to potentiate a strong fungicidal effect when combined with fungistatic fluconazole [144].…”

Small molecules for combating multidrug-resistant superbug Candida auris infections

“…further evaluated the activity of mefloquine derivatives, and they identified several compounds with improved potency. Among these, compound 4377 ( 37 ) showed the best activity against five C. auris isolates (MIC range: 2–4 μg/mL) 138 . However, this compound was still less active than caspofungin and amphotericin B. Mefloquine derivatives acted by multi-targeting mechanisms in which interference with the functions of mitochondria and vacuoles was preliminarily confirmed 138 .…”