Abstract
Fungal infections, such as candidiasis caused by Candida, pose a problem of growing medical concern. In developed countries, the incidence of Candida infections is increasing due to the higher survival of susceptible populations, such as immunocompromised patients or the elderly. Existing treatment options are limited to few antifungal drug families with efficacies that vary depending on the infecting species. In this context, the emergence and spread of resistant Candida isolates are being increasingly reported. Understanding how resistance can evolve within naturally susceptible species is key to developing novel, more effective treatment strategies. However, in contrast to the situation of antibiotic resistance in bacteria, few studies have focused on the evolutionary mechanisms leading to drug resistance in fungal species. In this review, we will survey and discuss current knowledge on the genetic bases of resistance to antifungal drugs in Candida opportunistic pathogens. We will do so from an evolutionary genomics perspective, focusing on the possible evolutionary paths that may lead to the emergence and selection of the resistant phenotype. Finally, we will discuss the potential of future studies enabled by current developments in sequencing technologies, in vitro evolution approaches, and the analysis of serial clinical isolates.
Highlights
From the estimated 1.5 million fungal species, around 300 have been reported to present virulence towards humans, even if sporadically [1]
Species belonging to the genera Candida, Aspergillus, and Cryptococcus are the most prevalent cause of invasive infections, with Candida being responsible for the most common invasive fungal disease in developed countries—candidiasis [3]
The four most common Candida (C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis) can account for more than 80% of the cases, there is a long list with over 30 Candida that have been identified as candidemia agents [9], and the list keeps expanding
Summary
From the estimated 1.5 million fungal species, around 300 have been reported to present virulence towards humans, even if sporadically [1]. There are only four major classes of antifungals in clinical use: azoles, polyenes, echinocandins, and pyrimidine analogs [10] This situation alarmingly decreases the chances of a successful treatment and increases the possibilities of a fatal outcome if the infecting pathogen is resistant to one or multiple drugs. To the problem of the intrinsic variation of drug susceptibility among different Candida, we need to add the emerging issue of acquired resistance, which refers to the ability of yeasts to evolutionarily develop mechanisms that lower their susceptibility towards a given drug [11] This process generally involves mutations ranging from chromosomal re-arrangements to point mutations. We will focus on how the advent of genomics technologies is allowing us to study these processes on unprecedented levels of scale and resolution, and how possible future studies could help us further our understanding of the evolutionary emergence of drug resistance in yeasts
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