Combinatorial strategies for combating invasive fungal infections

Abstract

Invasive fungal infections are an important cause of human mortality and morbidity, particularly for immunocompromised populations. However, there remains a paucity of antifungal drug treatments available to combat these fungal pathogens. Further, antifungal compounds are plagued with problems such as host toxicity, fungistatic activity, and the emergence of drug resistance in pathogen populations. A promising therapeutic strategy to increase drug effectiveness and mitigate the emergence of drug resistance is through the use of combination drug therapy. In this review we describe the current arsenal of antifungals in medicine and elaborate on the benefits of combination therapy to expand our current antifungal drug repertoire. We examine those antifungal combinations that have shown potential against fungal pathogens and discuss strategies being employed to discover novel combination therapeutics, in particular combining antifungal agents with non-antifungal bioactive compounds. The findings summarized in this review highlight the promise of combinatorial strategies in combatting invasive mycoses.

Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction

“…Drugs toxicity in the CBM treatment and the increase of resistant strains have driven studies on a combined therapy 54,55 . The benefits of this therapy are well-known and include a broad spectrum efficacy, greater potency than monotherapy, reduction emergence of resistance as well as improvements in both safety and tolerability [56][57][58] . Considering ritonavir was the most effective in inhibiting peptidase activity, cellular growth and fungal viability after macrophage interaction, we also evaluated its action in combination with classical antifungal drugs against P. verrucosa.…”

New facets of antifungal therapy

“…Unfortunately, combination antifungal therapy has been shown to improve outcomes in few clinical scenarios. 13 Furthermore, adverse drug effects and drug interactions are more likely with combination therapy.…”

New pathogens, new tricks: emerging, drug‐resistant fungal pathogens and future prospects for antifungal therapeutics

“…Combination drug therapy is another promising therapeutic strategy for the treatment of fungal infections, as well as many other infectious and noncommunicable diseases. [243][244][245] Combination therapies can improve the effectiveness of drug treatment and may limit or prevent the emergence of drug resistance, [246][247][248][249][250] making this strategy of particular interest for emerging and highly drug-resistant fungal pathogens. Combination therapy has been proposed as a treatment option for highly drug-resistant fungal pathogens, including Fusarium and Scedosporium species, where treatment with combinations of existing antifungals has shown promising results as effective therapeutics, 177,178,251 as well as combination therapy between antifungals and antiparasitics.…”