Antifungal Activity of Novel Formulations Based on Terpenoid Prodrugs against C. albicans in a Mouse Model.

Suvidha Menon,Ivana Cacciatore,Ketankumar Patel,Blase Billack,Xiuyi Liang,Lisa Marinelli,Richa Vartak,Antonio Di Stefano

doi:10.3390/pharmaceutics13050633

Suvidha Menon, Ivana Cacciatore + Show 6 more

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https://doi.org/10.3390/pharmaceutics13050633

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Journal: Pharmaceutics	Publication Date: Apr 29, 2021
Citations: 12	License type: CC BY 4.0

Affiliation: St. John's University, University of Chieti-Pescara

Abstract

Carvacrol (CAR), a phenolic monoterpenoid, has been extensively investigated for its antimicrobial and antifungal activity. As a result of its poor physicochemical properties, water soluble carvacrol prodrugs (WSCPs) with improved water solubility were previously synthesized and found to possess antimicrobial activity. Here, three novel CAR analogs, WSCP1, WSCP2, and WSCP3, were tested against fluconazole (FLU)-sensitive and -resistant strains where they showed greater antifungal activity than CAR against C. albicans. The probable mechanism by which the CAR prodrugs exert the antifungal activity was studied. Results from medium acidification assays demonstrated that the CAR and its synthetically designed prodrugs inhibit the yeast plasma membrane H+-ATPase (Pma1p), an essential target in fungi. In other words, in vitro data indicated that CAR analogs can prove to be a better alternative to CAR considering their improved water solubility. In addition, CAR and WSCP1 were developed into intravaginal formulations and administered at test doses of 50 mg/kg in a mouse model of vulvovaginal candidiasis (VVC). Whereas the CAR and WSCP1 formulations both exhibited antifungal efficacy in the mouse model of VVC, the WSCP1 formulation was superior to CAR, showing a remarkable decrease in infection by ~120-fold compared to the control (infected, untreated animals). Taken together, a synthetically designed prodrug of CAR, namely WSCP1, proved to be a possible solution for poorly water-soluble drugs, an inhibitor of an essential yeast pump in vitro and an effective and promising antifungal agent in vivo.

Highlights

Opportunistic fungal infections primarily caused by Candida albicans (C. albicans) are common
The various evolved mechanisms to evade human immunity and the metabolic flexibility of C. albicans, the pharmacological limitations of antifungal drugs, and the growing emergence of FLUresistant as well as multidrug-resistant strains in immunocompromised patients justifies the relevance of investigation of novel antifungal targets [1,2]
Our study showed that CAR and WSCP1 inhibits proton pump extrusion by

Summary

Introduction

Opportunistic fungal infections primarily caused by Candida albicans (C. albicans) are common. Despite being a commensal colonizer in various human niches (the oral mucosa, the gut, the vaginal tract, and the skin), C. albicans can successfully evolve as a pathogen because of its adaptability to the changing host microbiome (such as antibiotic treatment or when the host becomes debilitated or immunocompromised). The standard antifungal drug, fluconazole (FLU), is fungistatic in nature, and is a concern to immunocompromised patients. The high mortality rates associated with systemic infection or blood-borne candidiasis is another growing concern. The various evolved mechanisms to evade human immunity and the metabolic flexibility of C. albicans, the pharmacological limitations of antifungal drugs, and the growing emergence of FLUresistant as well as multidrug-resistant strains in immunocompromised patients justifies the relevance of investigation of novel antifungal targets [1,2]. The various evolved mechanisms to evade human immunity and the metabolic flexibility of C. albicans, the pharmacological limitations of antifungal drugs, and the growing emergence of FLUresistant as well as multidrug-resistant strains in immunocompromised patients justifies the relevance of investigation of novel antifungal targets [1,2]. 4.0/).

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