Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

Abstract

The incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active against Cryptococcus neoformans in vitro and had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

Difficult but Not Impossible: in Search of an Anti-Candida Vaccine

“…The molecule used against them is mannose-binding lectin (MBL), a protein that is synthesized in the liver and involved in complement cascade activation. Investigations of its function have found MBL-induced agglutination in the yeast Recombinant heat shock proteins: r-hsp90-CA [9,11] Laminarin: CRM197 [12] Replicative aging [23][24][25] Respiratory pathways: Mir1 [26] Sphingolipid metabolism: BHBM, D13 [27] Micafungin activated metacaspase complexes [28] Tricyclic antidepressants [16] Genetically engineered organisms: Lactobacillus casei containing the Eno1p antigen [29] phase to treat both C. glabrata and C. albicans. This was achieved through binding to the mannoproteins covering the fungal cell surface, inducing complement activation [15•].…”

“…In a study conducted with the synthetic drug, BHBM, an assay showed dose-dependent killing of C. neoformans. Mice subjects treated with BHBM and its derivative D13 survived after infection with live C. albicans [27]. Research into this avenue of fungal vaccination is one of the first to clear Phase II trials.…”

Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

“…If this transport is blocked, IPCs or/and GlcCer synthesis will not occur. Therefore, a drug targeting the transport of vesicles containing ceramide from the ER to the Golgi (e.g., [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (known as BHBM)) will significantly impact the synthesis of complex sphingolipids, even though the compound(s) does not directly inhibit any enzyme involved in the pathway illustrated in Figure 1 [ 29 , 30 , 31 , 32 ]. Similarly, compounds affecting fatty acid elongation, such as minimoidin, may also affect the synthesis of ceramide [ 33 ] because ceramide synthases are only able to incorporate specific fatty acids into DHS and PHS.…”

Present and Future Therapy of Cryptococcus Infections

“…Acylhydrazones such as BHBM target the non-mammalian sphingolipid pathway, which is critical for the virulence of C. neoformans and C. gattii . Three of nineteen derivatives of BHBM display potent in vitro activity against C. neoformans and one derivative showed antifungal activity with suitable CNS penetration in a non-immunocompromised murine model [ 32 ].…”