Chemosensitization as a Means to Augment Commercial Antifungal Agents

Abstract

Antimycotic chemosensitization and its mode of action are of growing interest. Currently, use of antifungal agents in agriculture and medicine has a number of obstacles. Foremost of these is development of resistance or cross-resistance to one or more antifungal agents. The generally high expense and negative impact, or side effects, associated with antifungal agents are two further issues of concern. Collectively, these problems are exacerbated by efforts to control resistant strains, which can evolve into a treadmill of higher dosages for longer periods. This cycle in turn, inflates cost of treatment, dramatically. A further problem is stagnation in development of new and effective antifungal agents, especially for treatment of human mycoses. Efforts to overcome some of these issues have involved using combinations of available antimycotics (e.g., combination therapy for invasive mycoses). However, this approach has had inconsistent success and is often associated with a marked increase in negative side effects. Chemosensitization by natural compounds to increase effectiveness of commercial antimycotics is a somewhat new approach to dealing with the aforementioned problems. The potential for safe natural products to improve antifungal activity has been observed for over three decades. Chemosensitizing agents possess antifungal activity, but at insufficient levels to serve as antimycotics, alone. Their main function is to disrupt fungal stress response, destabilize the structural integrity of cellular and vacuolar membranes or stimulate production of reactive oxygen species, augmenting oxidative stress and apoptosis. Use of safe chemosensitizing agents has potential benefit to both agriculture and medicine. When co-applied with a commercial antifungal agent, an additive or synergistic interaction may occur, augmenting antifungal efficacy. This augmentation, in turn, lowers effective dosages, costs, negative side effects and, in some cases, countermands resistance.

Sensitization of Candida albicans biofilms to fluconazole by terpenoids of plant origin

“…Few attempts have been made to study the anti-biofilm activities of terpenoids in combination with antifungal drugs (Khan and Ahmad, 2012). A combinatorial approach in antifungal therapy offers several potential advantages like increased potency, reduced dosages of individual drugs, minimized toxicities, and prevention of the emergence of drug-resistant mutant strains (Campbell et al, 2012;Shinde et al, 2013b). Carvacrol, eugenol and thymol are major constituents of essential oils derived from plants, especially of the genus Oreganum.…”

Octyl Gallate as an Intervention Catalyst to Augment Antifungal Efficacy of Caspofungin

“…chemosensitizer (intervention catalyst), with a commercial drug greatly enhances the efficacy of the co-applied drug [8]. The key advantage of chemosensitization is that, in contrast to combination therapy, which is a co-application of two or more commercial antimycotic drugs, a chemosensitizer itself does not have to possess a high degree of antifungal potency.…”

“…The key advantage of chemosensitization is that, in contrast to combination therapy, which is a co-application of two or more commercial antimycotic drugs, a chemosensitizer itself does not have to possess a high degree of antifungal potency. However, chemosensitization not only enhances the antifungal efficacy of the co-applied drug, but also mitigates pathogen resistance to conventional drugs [8]. Therefore, chemosensitization-based intervention could complement current antifungal practices, such as combination therapy.…”

Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections

“…This group of antifungal agents includes fluconazole, itraconazole, and, more recently, voriconazole and posaconazole. All these drugs may be administered to treat systemic mycoses (20). Fluconazole has fewer side effects than ketoconazole and may be used for the treatment of candidiasis and maintenance therapy for cryptococcal meningitis (21).…”