Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens

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.

The transcriptional aftermath in two independently formed hybrids of the opportunistic pathogenCandida orthopsilosis

“…The incidence of human fungal infections has steadily increased during the past decade, leading to recognition of their relevance in global epidemiology (Pfaller and Diekema 2007). Numerous factors may underlie this growing prevalence including, among others, increased number of immunocompromised individuals (elderly people, neonates, HIV, patients, etc) (Pfaller and Diekema 2007), emergence of drug resistance associated with extensive use of antimycotic agents (Pfaller et al 2009; Ksiezopolska and Gabaldón 2018), globalization (Mixão and Gabaldón 2018; Callaghan and Guest 2015), and climate change (Garcia-Solache and Casadevall 2010). The rising incidence of mycoses is also coupled to the identification of a larger number of etiological agents, including so called emergent pathogens that are increasingly identified in the clinics (Gabaldón, Naranjo-Ortíz, and Marcet-Houben 2016; Papon et al 2013).…”

Utilizing Liposomal Quercetin and Gallic Acid in Localized Treatment of Vaginal Candida Infections

“…Therapeutic approaches for VVC comprise both local and oral administration of different azole drugs, such as fluconazole, ketoconazole and clotrimazole [6], that are able to reduce symptoms of an initial infection in a large number of patients [3]. Unfortunately, since all azoles have a similar fungistatic effect on Candida spp., the cells exposed repetitively to these antifungals may adapt to drug pressure and became resistant [7]. Taking into consideration the emerging problem of drug resistance, as well as the high incidence of VVC, it is clear that new therapeutic strategies based on both administration of alternative antimicrobials and development of advanced delivery systems, are extremely desirable.…”

Azole Resistance and Detection of the ERG11 Gene in Clinical Candida albicans Isolated from Pregnant Women with Vulvovaginitis Attending Federal Medical Centre, Yenagoa, Nigeria

“…Of recent, there has been a marked increase in the frequency of azole treatment failures in patients with candidiasis and are being treated for long-term antimycotic therapy, this has posed a serious concern in its efficacious use in chemotherapy. Reasons had been that Candida can acquire multidrug resistance (MDR) during the course of the therapy [1,2]. Various authors have documented that Candida species possessed different mechanisms of resistance to azole antifungal agents and these mechanisms are categorised mainly as (i) changes in the cell wall or plasma membrane, which can lead to impaired drug (azole) uptake [3,4]; (ii) alterations in the affinity of the drug target Erg11p (lanosterol 14alpha-demethylase) especially to azoles or in the cellular content of Erg11p due to target site mutation or overexpression of the ERG11 gene [4,5,6,7] and (iii) the efflux of drugs mediated by membrane transport proteins belonging to the ATP-binding cassette (ABC) transporters, namely CDR1 and CDR2 or to the major facilitator superfamily (MFS) transporter, CaMDR1 [8,9].…”

“…According to Rodrigues and colleagues (2017) [3], and Sardi et al [10], biofilm-associated Candida shows uniform resistance to a wide spectrum of antifungal drugs. Furthermore, studies conducted by Ksiezopolska and Gabaldón [1] revealed that a combination of different resistance mechanisms is responsible for drug resistance in clinical isolates of Candida species.…”