The antifungal pipeline: a reality check

Abstract

Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies - polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) - in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

Figure 1. Currently available antifungal compounds and future derivatives thereof

There are currently four classes of antifungals available: polyenes, flucytosine, azoles and echinocandins. Improvements have been made to three of these classes to increase efficacy or reduce toxicity. Future generations of these classes of compounds are in development.

Figure 2. Antifungal targets

Numerous molecules can be attacked by antifungals, including fungus-specific components of the cell wall or cell membrane, or processes such as metabolism, DNA synthesis, mitochondrial function or the stress response. Investigational antifungal agents targeting these components are indicated in light blue boxes, and approved antifungal classes are indicated in dark blue boxes. Some antifungals exert their specificity by being taken up by fungus-specific transporters. Acs1, acetyl-CoA synthetase 1; BHBM, N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide; Dhodh, dihydroorotate dehydrogenase; HOG, high-osmolarity glycerol; Hsp90, heat shock protein 90; Icl, isocitrate lyase; Pdk1, 3-phosphoinositide-dependent protein kinase 1; PMN, polymorphonuclear; UDP, uridine diphosphate.