Antifungal Activity of Minocycline and Azoles Against Fluconazole-Resistant Candida Species.

Jingwen Tan,Haiyan Shi,Lihua Tan,Yi Sun,Shaojie Jiang,Xiuli Wang,Lianjuan Yang

doi:10.3389/fmicb.2021.649026

Jingwen Tan, Haiyan Shi + Show 5 more

Open Access

https://doi.org/10.3389/fmicb.2021.649026

Copy DOI

Abstract

Candida species are the most common fungal pathogens to infect humans, and can cause life-threatening illnesses in individuals with compromised immune systems. Fluconazole (FLU) is the most frequently administered antifungal drug, but its therapeutic efficacy has been limited by the emergence of drug-resistant strains. When co-administered with minocycline (MIN), FLU can synergistically treat clinical Candida albicans isolates in vitro and in vivo. However, there have been few reports regarding the synergistic efficacy of MIN and azoles when used to treat FLU-resistant Candida species, including Candida auris. Herein, we conducted a microdilution assay wherein we found that MIN and posaconazole (POS) showed the best in vitro synergy effect, functioning against 94% (29/31) of tested strains, whereas combinations of MIN+itraconazole (ITC), MIN+voriconazole (VOR), and MIN+VOR exhibited synergistic activity against 84 (26/31), 65 (20/31), and 45% (14/31) of tested strains, respectively. No antagonistic activity was observed for any of these combinations. In vivo experiments were conducted in Galleria mellonella, revealing that combination treatment with MIN and azoles improved survival rates of larvae infected with FLU-resistant Candida. Together, these results highlight MIN as a promising synergistic compound that can be used to improve the efficacy of azoles in the treatment of FLU-resistant Candida infections.

Highlights

Invasive fungal infections represent an increasingly common threat to human health (Firacative, 2020), with Candida species serving as the leading cause of fungal infections and the fourth most prominent source of bloodstream infections globally, resulting in over 750,000 infections and a 40% mortality rate globally each year (McCarty and Pappas, 2016; Tsay et al, 2020)
Minocycline was first identified as an inhibitor of C. albicans growth in 1974 (Waterworth, 1974), and several studies have further highlighted the antifungal activity of this compound
Shi et al (2010) and Gu et al (2018) demonstrated the ability of MIN to synergize with FLU against C. albicans in vitro and in vivo and Gao et al (2013) observed synergy between tetracycline and FLU when treating C. albicans biofilms

Summary

Introduction

Invasive fungal infections represent an increasingly common threat to human health (Firacative, 2020), with Candida species serving as the leading cause of fungal infections and the fourth most prominent source of bloodstream infections globally, resulting in over 750,000 infections and a 40% mortality rate globally each year (McCarty and Pappas, 2016; Tsay et al, 2020). Candida albicans is the leading pathogenic member of this family, accounting for roughly half of these infections, followed by Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei. These five species cause 90% of candidaemia and other forms of invasive candidiasis (Goemaere et al, 2018). Candida auris is an emerging pathogen, and 93% of these isolates are resistant to FLU with varying levels of resistance to other azoles, making it a dangerous nosocomial pathogen with mortality rates of 30–60% (Berkow and Lockhart, 2017; Forsberg et al, 2019). There is a clear need to identify reliable antifungal agents or compounds capable of enhancing the antifungal activity of extant compounds in order to improve patient outcomes

Methods

Results

Conclusion