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Updated: Sep 26, 2025
High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
Published on: May 21, 2018
Augmenting Azoles with Drug Synergy to Expand the Antifungal Toolbox
1School of Life and Environmental Sciences and Sydney ID, University of Sydney, Camperdown, NSW 2006, Australia.
Abstract:
Fungal infections impact the lives of at least 12 million people every year, killing over 1.5 million. Wide-spread use of fungicides and prophylactic antifungal therapy have driven resistance in many serious fungal pathogens, and there is an urgent need to expand the current antifungal arsenal. Recent research has focused on improving azoles, our most successful class of antifungals, by looking for synergistic interactions with secondary compounds. Synergists can co-operate with azoles by targeting steps in related pathways, or they may act on mechanisms related to resistance such as active efflux or on totally disparate pathways or processes. A variety of sources of potential synergists have been explored, including pre-existing antimicrobials, pharmaceuticals approved for other uses, bioactive natural compounds and phytochemicals, and novel synthetic compounds. Synergy can successfully widen the antifungal spectrum, decrease inhibitory dosages, reduce toxicity, and prevent the development of resistance. This review highlights the diversity of mechanisms that have been exploited for the purposes of azole synergy and demonstrates that synergy remains a promising approach for meeting the urgent need for novel antifungal strategies.
Insights
Fungal infections are a major global health threat. Combining existing antifungal azoles with other compounds, known as synergy, offers a promising strategy to combat drug resistance and improve treatment outcomes.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Drug Discovery
Background:
- Fungal infections cause significant mortality and morbidity worldwide.
- Increasing antifungal resistance necessitates novel therapeutic strategies.
- Azoles are a cornerstone of antifungal therapy but face resistance challenges.
Purpose of the Study:
- To review the mechanisms and sources of synergistic interactions with azole antifungals.
- To highlight the potential of synergy to overcome antifungal resistance.
- To underscore the importance of synergy in expanding the antifungal arsenal.
Main Methods:
- Literature review of studies investigating azole synergy.
- Analysis of diverse sources for potential synergistic compounds.
- Examination of various mechanisms underlying synergistic effects.
Main Results:
- Synergistic compounds can target related pathways, resistance mechanisms (e.g., efflux pumps), or unrelated cellular processes.
- Potential synergists are found in existing antimicrobials, repurposed drugs, natural products, and synthetic compounds.
- Synergy broadens antifungal spectrum, reduces required drug doses, and mitigates toxicity.
Conclusions:
- Azole synergy is a versatile approach to combatting fungal infections.
- Exploiting synergistic interactions is crucial for developing new antifungal strategies.
- Synergy offers a viable path to address the urgent need for effective treatments against resistant fungal pathogens.
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