New Approaches for Cryptococcosis Treatment

Abstract

Cryptococcosis is an important opportunistic infection and a leading cause of meningitis in patients with HIV infection. The antifungal pharmacological treatment is limited to amphotericin B, fluconazole and 5- flucytosine. In addition to the limited pharmacological options, the high toxicity, increased resistance rate and difficulty of the currently available antifungal molecules to cross the blood-brain barrier hamper the treatment. Thus, the search for new alternatives for the treatment of cryptococcal meningitis is extremely necessary. In this review, we describe the therapeutic strategies currently available, discuss new molecules with antifungal potential in different phases of clinical trials and in advanced pre-clinical phase, and examine drug nanocarriers to improve delivery to the central nervous system.

Keywords: Cryptococcus; antifungal; blood–brain barrier; central nervous system; cryptococcal meningitis; drug delivery systems; drug repurposing; nanocarriers; nanotechnology; synthetic molecules.

Figure 1

Conventional antifungals and new molecules for cryptococcosis treatment. Amphotericin B (AMB) and azoles inhibit ergosterol and its biosynthesis, respectively, and flucytosine inhibits the nucleic acids synthesis. New molecules acting on non-conventional targets or different structures of fungal cells may have antifungal effects. Erg11 (or Cyp51)—cytochrome P450-dependent lanosterol C14-alpha-demethylase; AcS—Acetyl CoA synthetase; Hsp90—Heat shock protein 90.

Figure 2

Schematic representation of nanocarriers, their surface modification and possible routes of transport across the blood–brain barrier (BBB). (A) Nanocarriers frequently employed for drug delivery to the central nervous system. (B) Examples of nanocarrier surface modification to improve passage through the BBB; (C) Possible routes of nanocarrier-mediated transport across the BBB. 1—Nanocarrier-mediated transport; 2—Paracellular pathway, which can result from the ability of a nanocarrier and/or its components to open tight junctions; 3—Adsorption-mediated transcytosis; 4—Transcellular pathway, which might result from the ability of nanocarrier components to improve membrane permeability; 5—Receptor-mediated transcytosis. PEG: polyethyleneglycol; vitE TPGS: D-α-tocopherol polyethylene glycol 1000 succinate.