Bioinformatic survey of ABC transporters in dermatophytes

Gadzalski, Marek; Ciesielska, Anita; Stączek, Paweł

doi:10.1016/j.gene.2015.10.064

Cited by 10 publications

(12 citation statements)

References 51 publications

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“…Therapeutic failures, due to the development of fungal resistance, are often associated with efflux pumps (Martinez-Rossi et al, 2008;Prasad et al, 2006). In dermatophytes, dozens of genes contain the ABC transporter domain (Gadzalski et al, 2016). The pdr1 (pleiotropic drug resistance, PDR) gene of Trichophyton interdigitale, previously named mdr1, encodes an ABC transporter that is over-expressed in the presence of several antifungal drugs (Cervelatti et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes

Martins

Franceschini

Jacob

et al. 2016

Journal of Medical Microbiology

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Genomic sequencing of several dermatophyte species has revealed that they show small differences in genetic content and genome organization, although each fungus has adapted to specific niches. Thus, it seemed relevant to compare gene expression between species. Here, we examined the transcription modulation of three ATP-binding cassette (ABC) transporter genes (pdr1, mdr2 and mdr4), which code for membrane transporter proteins in four species of Trichophyton; T. interdigitale, T. rubrum, T. tonsurans and T. equinum. These fungal species were challenged with sub-lethal doses of griseofulvin, itraconazole, terbinafine and amphotericin B. A mutant strain of T. interdigitale, Dmdr2, was also analysed for the modulation of pdr1 and mdr4 genes to evaluate the possible functional interaction among these three genes. Disruption of the mdr2 gene resulted in the accumulation of high levels of mdr4 transcripts when challenged with griseofulvin, suggesting that the mdr4 gene is compensating for the inactivation of mdr2 by providing resistance to this antifungal. Although the three ABC transporter genes have high homology between the four dermatophytes analysed, it is likely that they have specific functions, suggesting that the action of each drug is dependent on other factors inherent to each species. Our data suggest that these ABC transporter genes act synergistically in dermatophytes, and they may compensate for one another when challenged with antifungal drugs. This may be an important cause of therapeutic failure when treating fungal infections.

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Section: Introductionmentioning

confidence: 99%

Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes

Martins

Franceschini

Jacob

et al. 2016

Journal of Medical Microbiology

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“…The availability of the genome sequence of different dermatophytes has revealed a homogeneous group of these transporters, which exhibits very low genetic diversity with only a few exclusive genes in each analyzed species ( Burmester et al, 2011 ; Martinez et al, 2012 ). The analysis of seven of these dermatophyte genomes identified a large number of encoded ABC transporter domains with many of the associated genes having counterparts in all studied species, suggesting that ABC transporter genes act equivalently, despite the phenotypic and adaptive uniqueness of each species ( Gadzalski et al, 2016 ).…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

“…For example, the transcriptional profiling of the pdr1, mdr2 , and mdr4 genes of four species of Trichophyton : T. equinum, T. interdigitale, T. rubrum , and T. tonsurans , did not reflect the intrinsic phylogenetic relationship among these fungi, nor was a functional correlation revealed between species and the efflux modulation under the tested conditions. However, the evaluated genes appear to work synergistically, leading to the understanding that one mdr gene may be compensated by others as related to extrusion activity ( Martinez-Rossi et al, 2008 ; Gadzalski et al, 2016 ; Martins et al, 2016 ).…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus

et al. 2018

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Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.

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“…The other possible cause of resistance to these antifungals is associated with the activity of ABC transporters (ATP‐binding cassettes transporters) 32,33 . These transporters act effectively in drug efflux, decreasing the intracellular accumulation of cytotoxic compounds, thus playing a significant role in multidrug resistance (MDR) mechanisms 25,33‐36 . Unfortunately, the direct involvement of these transporters in azole efflux has yet to be clearly proved, especially in the context of dermatophytes.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the direct involvement of these transporters in azole efflux has yet to be clearly proved, especially in the context of dermatophytes. In these keratinophilic fungi, dozens of genes contain the ABC transporter domain, and a presumed role in drug resistance has been demonstrated for some of the genes, that is, PDR1 (pleiotropic drug resistance, PDR ; previously MDR1 ), MDR2 (multidrug resistance protein) and MDR4 (ABC multidrug transporter) 32,33,35,37 . Moreover, there are literature reports describing clinical dermatophyte isolates with simultaneous resistance to both azoles and terbinafine 32 .…”

Section: Introductionmentioning

confidence: 99%

Complementary effect of mechanism of multidrug resistance in Trichophyton mentagrophytes isolated from human dermatophytoses of animal origin

Gnat

Łagowski

Nowakiewicz

et al. 2021

Mycoses

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Background Dermatophytoses have gained interest worldwide due to the increased resistance to terbinafine and azoles and difficulty in management of these refractory diseases. Objectives In this study, we identified and analysed Trichophyton mentagrophytes clinical isolates obtained from humans with infections of animal origin. Methods We used quantitative real‐time PCR (qRT‐PCR) to examine the transcriptional modulation of three MDR genes (PDR1, MDR2 and MDR4) and analysed squalene epoxidase (SQLE) gene sequences from multidrug‐resistant Trichophyton mentagrophytes isolates. Results The expression profile revealed a 2‐ to 12‐fold increase in mRNA accumulation in the presence of any of the antifungals, compared to cells incubated without drugs. A statistically significant relationship between the isolates exposed to itraconazole and increased expression of the tested genes was revealed. Substantially lower transcription levels were noted for cells exposed to luliconazole, that is, a third‐generation azole. Additionally, in the case of 50% of terbinafine‐resistant strains, Leu397Phe substitution in the SQLE gene was detected. Furthermore, the reduced susceptibility to itraconazole and voriconazole was overcome by milbemycin oxime. Conclusions In conclusion, our study shed more light on the role of the ABC transporter family in T. mentagrophytes, which, if overexpressed, can confer resistance to single azole drugs and even cross‐resistance. Finally, milbemycin oxime could be an interesting compound supporting treatment with azole drugs in the case of refractory dermatomycoses.

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Bioinformatic survey of ABC transporters in dermatophytes

Cited by 10 publications

References 51 publications

Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes

Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes

Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus

Complementary effect of mechanism of multidrug resistance in Trichophyton mentagrophytes isolated from human dermatophytoses of animal origin

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