A state-of-the-art review and prospective therapeutic applications of prenyl flavonoids as chemosensitizers against antifungal multidrug resistance in Candida albicans

SANTI, MARIA DANIELA; ORTEGA, MARÍA GABRIELA; PERALTA, MARIANA ANDREA

CURRENT MEDICINAL CHEMISTRY.

BENTHAM SCIENCE PUBL LTD

Año: 2022 vol. 29

0929-8673

According to a recent definition, multidrug resistance (MDR) is an acquired non-susceptibility to at least one agent in three or more antimicrobial categories. MDR in the opportunistic pathogen Candida albicans is defined as non-susceptibility at least one agent in two or more drug classes. This phenomenon has been increasingly reported since the rise in the incidence of fungal infections in immunocompromised patients at the end of the last century.Chemosensitization emerged as a valid tool to combat MDR in microorganisms causing infections in which first-line antimicrobial treatments were ineffective. This approach allows overcoming MDR and chemosensitizing resistant strains to antimicrobials. After the discovery of efflux pump overexpression as a principal mechanism causing MDR in Candida strains, drug discovery targeting fungal efflux transporters has had a growing impact. Chemosensitization aims to enhance azole intracellular concentrations through combination therapy with transporter inhibitors. Consequently, the use of drug efflux inhibitors combined with the antifungal agent will sensitize the pathogen. As a result, the use of lower drug concentrations will reduce possible adverse effects on the host. Through an extensive revision of the literature, this review aims to provide an exhaustive and critical analysis of the studies carried out in the past two decades, regarding the chemosensitization strategy using phytocompounds to cope with multidrug resistance in C. albicans. In this review, we especially emphasize flavonoids, due to their therapeutic potential as chemosensitizers and within them; we highlight the importance of prenylflavonoids due to their particular chemical and pharmacological characteristics. This work provides a comprehensive review of the research carried out on the inhibition of drug-efflux membrane transporters by prenylated flavonoids and the interactions of these phytocompounds with azole antifungals as an approach to chemosensitize multidrug-resistant C. albicans strains. Besides, this review presents the state-of-the-art and perspectives in the discovery of new natural antifungal agents and proposes the need for further research on the potential of prenyl flavonoids as inhibitors of drug-efflux mediated fungal resistance.