Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Forastiero, A.; Mesa-Arango, Ac C.; Alastruey‐Izquierdo, Ana; Alcàzar-Fuoli, Laura; Bernal‐Martínez, Leticia; Peláez, Teresa; Lopez, Jf F.; Grimalt, Joan O.; Gómez-López, Alicia; Cuesta, Isabel; Zaragoza, Óscar; Mellado, Emilia

doi:10.1128/aac.00477-13

Cited by 99 publications

(101 citation statements)

References 73 publications

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“…Growth curves were performed in the pres- ence of different rotenone concentrations, including a control with an equivalent concentration of the solvent in which rotenone is prepared (DMSO). In this experiment, we used C. tropicalis as the model (strain ATCC 750) because we had two AMB-resistant isolates available from this species, which have been extensively characterized below and in previous findings from our group (51). Rotenone inhibited C. tropicalis growth at concentrations between 0.62 and 0.156 mM (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Recent findings suggest that the AMB effect on the cell membrane is due to ergosterol sequestration (34). Recent data have demonstrated that C. tropicalis strains with reduced susceptibility to AMB do not contain ergosterol in their membranes (51,66); therefore, they are also resistant to azoles. Ergosterol depletion from the cell membrane poses a problem, since this molecule is required to maintain an optimal membrane structure.…”

Section: Discussionmentioning

confidence: 99%

“…We chose several strains (4 to 7) from the main species of pathogenic yeasts and 44 isolates in total (see Table 1). In addition, we used two Candida tropicalis isolates with reduced susceptibility to AMB: ATCC 200956 and CL-6835 (from the yeast collection of the Mycology Reference Laboratory of the Spanish National Centre for Microbiology [51]). Another C. tropicalis strain, TP-13650, was resistant to azoles but susceptible to AMB (51).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, we used two Candida tropicalis isolates with reduced susceptibility to AMB: ATCC 200956 and CL-6835 (from the yeast collection of the Mycology Reference Laboratory of the Spanish National Centre for Microbiology [51]). Another C. tropicalis strain, TP-13650, was resistant to azoles but susceptible to AMB (51). Yeast cells were routinely grown in liquid Sabouraud medium (Oxoid, Ltd., Basingstoke, Hampshire, England) at 30°C with moderate shaking (150 rpm).…”

Section: Methodsmentioning

confidence: 99%

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The Production of Reactive Oxygen Species Is a Universal Action Mechanism of Amphotericin B against Pathogenic Yeasts and Contributes to the Fungicidal Effect of This Drug

Mesa-Arango

Trevijano-Contador

Román

et al. 2014

Antimicrob Agents Chemother

167

143

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e Amphotericin B (AMB) is an antifungal drug that binds to ergosterol and forms pores at the cell membrane, causing the loss of ions. In addition, AMB induces the accumulation of reactive oxygen species (ROS), and although these molecules have multiple deleterious effects on fungal cells, their specific role in the action mechanism of AMB remains unknown. In this work, we studied the role of ROS in the action mechanism of AMB. We determined the intracellular induction of ROS in 44 isolates of different pathogenic yeast species (Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, Candida krusei, Cryptococcus neoformans, and Cryptococcus gattii). We also characterized the production of ROS in AMB-resistant isolates. We found that AMB induces the formation of ROS in all the species tested. The inhibition of the mitochondrial respiratory chain by rotenone blocked the induction of ROS by AMB and provided protection from the killing action of the antifungal. Moreover, this phenomenon was absent in strains that displayed resistance to AMB. These strains showed an alteration in the respiration rate and mitochondrial membrane potential and also had higher catalase activity than that of the AMB-susceptible strains. Consistently, AMB failed to induce protein carbonylation in the resistant strains. Our data demonstrate that the production of ROS by AMB is a universal and important action mechanism that is correlated with the fungicidal effect and might explain the low rate of resistance to the molecule. Finally, these data provide an opportunity to design new strategies to improve the efficacy of this antifungal.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The Production of Reactive Oxygen Species Is a Universal Action Mechanism of Amphotericin B against Pathogenic Yeasts and Contributes to the Fungicidal Effect of This Drug

Mesa-Arango

Trevijano-Contador

Román

et al. 2014

Antimicrob Agents Chemother

167

143

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“…In C. tropicalis, overexpression of ERG11 associated with missense mutations has been described as the most frequent azole resistance mechanism in clinical isolates (7,8). However, the azole resistance mechanisms of C. tropicalis remain a matter of debate, and only five studies have been reported to date (7)(8)(9)(10)(11). In addition, there is a lack of substantial research on mutations in the transcription factor Upc2p of C. tropicalis, which can induce ERG11 overexpression and contribute to the development of fluconazole resistance in C. albicans (12)(13)(14).…”

mentioning

confidence: 99%

Resistance Mechanisms and Clinical Features of Fluconazole-Nonsusceptible Candida tropicalis Isolates Compared with Fluconazole-Less-Susceptible Isolates

Choi

Won

Shin

et al. 2016

Antimicrob Agents Chemother

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eWe investigated the azole resistance mechanisms and clinical features of fluconazole-nonsusceptible (FNS) isolates of Candida tropicalis recovered from Korean surveillance cultures in comparison with fluconazole-less-susceptible (FLS) isolates. Thirtyfive clinical isolates of C. tropicalis, comprising 9 FNS (fluconazole MIC, 4 to 64 g/ml), 12 FLS (MIC, 1 to 2 g/ml), and 14 control (MIC, 0.125 to 0.5 g/ml) isolates, were assessed. CDR1, MDR1, and ERG11 expression was quantified, and the ERG11 and UPC2 genes were sequenced. Clinical features of 16 patients with FNS or FLS bloodstream isolates were analyzed. Both FNS and FLS isolates had >10-fold higher mean expression levels of CDR1, MDR1, and ERG11 genes than control isolates (P values of <0.02 for all). When FNS and FLS isolates were compared, FNS isolates had 3.4-fold higher mean ERG11 expression levels than FLS isolates (P ‫؍‬ 0.004), but there were no differences in those of CDR1 or MDR1. Of all 35 isolates, 4 (2 FNS and 2 FLS) and 28 (8 FNS, 11 FLS, and 9 control) isolates exhibited amino acid substitutions in Erg11p and Upc2p, respectively. Both FNS and FLS bloodstream isolates were associated with azole therapeutic failure (3/4 versus 4/7) or uncleared fungemia (4/6 versus 4/10), but FNS isolates were identified more frequently from patients with previous azole exposure (6/6 versus 3/10; P ‫؍‬ 0.011) and immunosuppression (6/6 versus 3/10; P ‫؍‬ 0.011). These results reveal that the majority of FNS C. tropicalis isolates show overexpression of CDR1, MDR1, and ERG11 genes, and fungemia develops after azole exposure in patients with immunosuppression. Candida tropicalis has become an important cause of bloodstream infections (BSIs) in seriously ill patients (1-3). Although C. tropicalis is usually susceptible to azole antifungals, 7 to 40% of clinical isolates have recently been reported to be resistant to azoles, particularly fluconazole (2-5). The mechanisms responsible for acquired azole resistance are well-characterized in Candida albicans and include mutations in the ERG11 gene, which encodes the drug target enzyme (lanosterol 14␣-demethylase), overexpression of ERG11, and overexpression of genes encoding efflux pumps (6). In C. tropicalis, overexpression of ERG11 associated with missense mutations has been described as the most frequent azole resistance mechanism in clinical isolates (7,8). However, the azole resistance mechanisms of C. tropicalis remain a matter of debate, and only five studies have been reported to date (7-11). In addition, there is a lack of substantial research on mutations in the transcription factor Upc2p of C. tropicalis, which can induce ERG11 overexpression and contribute to the development of fluconazole resistance in C. albicans (12)(13)(14).Fluconazole MIC distributions of wild-type C. tropicalis ranged from 0.125 to 64 g/ml following 24 h of incubation using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution (BMD) methods, and their modal MIC values were 0.125 to 0.5 g/ml (6). Recently, the CLSI es...

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Expanding the therapeutic options for Candida infections using novel inhibitors of secreted aspartyl proteases

Chakraborty

Rahate

Kumar

et al. 2022

Drug Development Research

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For widening the therapeutic options for Candida management, the druggability of Candida proteome was systematically investigated using an innovative pipeline of high-throughput data mining algorithms, followed by in vitro validation of the observations. Through this exercise, HIV-1 protease was found to share structural similarity with secreted aspartyl protease-3 (SAP3), a virulence protein of Candida.Using the molecular fingerprint of HIV-1 protease inhibitor GRL-09510, we performed virtual screening of peptidomimetic library followed by high-precision docking and MD simulations for discovery of SAP inhibitors. Wet-lab validation of the four shortlisted peptidomimetics revealed that two molecules, when used in combination with fluconazole, could significantly reduce the dosage of fluconazole required for 50% inhibition of Candida albicans. The SAP inhibitory activity of these peptidomimetics was confirmed through SAP assays and found to be on par with pepstatin A, a known peptidomimetic inhibitor of aspartyl proteases.

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Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Cited by 99 publications

References 73 publications

The Production of Reactive Oxygen Species Is a Universal Action Mechanism of Amphotericin B against Pathogenic Yeasts and Contributes to the Fungicidal Effect of This Drug

The Production of Reactive Oxygen Species Is a Universal Action Mechanism of Amphotericin B against Pathogenic Yeasts and Contributes to the Fungicidal Effect of This Drug

Resistance Mechanisms and Clinical Features of Fluconazole-Nonsusceptible Candida tropicalis Isolates Compared with Fluconazole-Less-Susceptible Isolates

Expanding the therapeutic options for Candida infections using novel inhibitors of secreted aspartyl proteases

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