Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets!

Abstract

Fungal infections caused by Candida, Aspergillus, and Cryptococcus species are an increasing problem worldwide, associated with very high mortality rates. The successful prevalence of these human pathogens is due to their ability to thrive in stressful host niche colonization sites, to tolerate host immune system-induced stress, and to resist antifungal drugs. This review focuses on the key role played by multidrug resistance (MDR) transporters, belonging to the ATP-binding cassette (ABC), and the major facilitator superfamilies (MFS), in mediating fungal resistance to pathogenesis-related stresses. These clearly include the extrusion of antifungal drugs, with C. albicans CDR1 and MDR1 genes, and corresponding homologs in other fungal pathogens, playing a key role in this phenomenon. More recently, however, clues on the transcriptional regulation and physiological roles of MDR transporters, including the transport of lipids, ions, and small metabolites, have emerged, linking these transporters to important pathogenesis features, such as resistance to host niche environments, biofilm formation, immune system evasion, and virulence. The wider view of the activity of MDR transporters provided in this review highlights their relevance beyond drug resistance and the need to develop therapeutic strategies that successfully face the challenges posed by the pleiotropic nature of these transporters.

Pleiotropy and epistasis within and between signaling pathways defines the genetic architecture of fungal virulence

“…Similar to this past study, we also identified pleiotropic QTGs contributing to more than one virulence-related trait examined here (including thermal tolerance and melanization), namely the genes RIC8 and SSK2. While our study did not share any of the previously implicated QTGs (Lin et al, 2006;Vogan et al, 2016), across several studies -not just those using QTL mapping strategies -observing pleiotropic effects of genes and pathways connected to virulence and virulence-associated traits seems to be a unifying phenomena (Shen et al, 2010;Fang et al, 2012;Tefsen et al, 2014;Lendenmann et al, 2015;Cavalheiro et al, 2018;So et al, 2019;Lev et al, 2019).…”

An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

“…In all cases described so far, the higher activity of MDR pumps is linked to their higher expression in the azole-resistant isolates [72]. In C. albicans and in C. glabrata the transcriptional regulation of these drug-efflux pumps is under a tight control of the pleiotropic drug resistance network (or PDR) that in C. glabrata is dependent of the CgPdr1 regulator [76] while in C. albicans is controlled by CaTac1 [77] ( Table 3).…”

“…The more studied drug efflux pumps linked to azole resistance are those belonging to the ATP-binding cassette (ABC) superfamily which include in C. albicans CaMdr1, CaCdr1 and CaCdr2 [55,56,71]; in C. glabrata, CgCdr1, CgCdr2 and CgPdh1 [59][60][61]; in C. krusei, CkAbc1 and CkAbc2 [69]; in C. parapsilosis CpCdr1 and in C. tropicalis CtCdr1 [42,46]. More recently, multi drug resistance (MDR) transporters belonging to the Major Facilitator Superfamily (MFS) have also been implicated in tolerance of different Candida species to azoles including CaMdr1 in C. albicans, C. parapsilosis and C. tropicalis [42,46,49] and CgTpo1_1, CgTpo3 and CgQdr2 in C. glabrata [72]. Although the influence of these transporters in mediating resistance in clinical isolates has not been studied at the same extent as those of the ABC superfamily, promising results had been obtained in a recent study showing a positive correlation between the expression of the C. glabrata CgAqr1, CgTpo1_1, CgTpo3 and CgQdr2 MFS-MDR transporters and resistance to clotrimazole [70].…”

“…Summary of the mechanisms of resistance registered in azole-resistant Candida isolates, as described in[40][41][42][43]72,[76][77][78][79]82,[85][86][87][88][89]92,93,96,[111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128].…”

Proteomic analysis of the inhibitory effect of chitosan on Penicillium expansum

“…Dxidative stress was also observed in chitosan treated U. maydis (Dlicón-Hernández et al, 2017); therefore, increased expression of these proteins may be associated with an imbalance of the intracellular redox state. Moreover, spot 25 was identified as an ABC multidrug transporter, which is known to be involved in extrusion of antifungal drugs (Cavalheiro et al, 2018). Ot has been assumed that chitosan could enter into fungi cell thereby causing physiological disturbance (Palma-Guerrero et al, 2009).…”