Augmenting Azoles with Drug Synergy to Expand The Antifungal Toolbox

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 ar-senal. 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 re-sistance like 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 dosag-es, 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 strate-gies.

A mechanism study on the synergistic effects of rifapentine and fluconazole against fluconazole-resistant Candida albicans in vitro

“…The development of new fungistatic agents is costly and time-consuming, which cannot catch up with the rate of fungal drug resistance [ 31 ]. Antifungal agents combined with non-antifungal agents can enhance antifungal activity and reduce fungal resistance and adverse reactions [ 28 , 32 , 33 ]. Therefore, the combination of antifungal and non-antifungal drugs has become a hot research topic in recent years.…”

Can Amphotericin B and Itraconazole Be Co-Delivered Orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses

“…This drug is characterised also by low aqueous solubility and a poor dissolution rate [25]. However, unlike AmB, ITR is currently available as hydroxypropyl-β-cyclodextrin-based suspensions and capsules containing coated pellets for oral administration and has demonstrated a very low toxicity [26,27]. Nevertheless, ITR could cause some mild adverse effects, including fluid retention, gastrointestinal intolerance and headache [28].…”