@article{SchielmannSzwedaGucwaetal.2017,
  author    = {Schielmann, Marta and Szweda, Piotr and Gucwa, Katarzyna and Kawczyński, Marcin and Milewska, Maria J. and Martynow, Dorota and Morschh{\"a}user, Joachim and Milewski, Sławomir},
  title     = {Transport deficiency is the molecular basis of \(Candida\) \(albicans\) resistance to antifungal oligopeptides},
  series = {Frontiers in Microbiology},
  volume    = {8},
  journal   = {Frontiers in Microbiology},
  doi       = {10.3389/fmicb.2017.02154},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173245},
  year      = {2017},
  abstract  = {Oligopeptides incorporating \(N3\)-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), an inhibitor of glucosamine-6-phosphate synthase, exhibited growth inhibitory activity against \(Candida\) \(albicans\), with minimal inhibitory concentration values in the 0.05-50 μg mL\(^{-1}\) range. Uptake by the peptide permeases was found to be the main factor limiting an anticandidal activity of these compounds. Di- and tripeptide containing FMDP (F2 and F3) were transported by Ptr2p/Ptr22p peptide transporters (PTR) and FMDP-containing hexa-, hepta-, and undecapeptide (F6, F7, and F11) were taken up by the oligopeptide transporters (OPT) oligopeptide permeases, preferably by Opt2p/Opt3p. A phenotypic, apparent resistance of \(C. albicans\) to FMDP-oligopeptides transported by OPT permeases was triggered by the environmental factors, whereas resistance to those taken up by the PTR system had a genetic basis. Anticandidal activity of longer FMDP-oligopeptides was strongly diminished in minimal media containing easily assimilated ammonium sulfate or L-glutamine as the nitrogen source, both known to downregulate expression of the OPT genes. All FMDP-oligopeptides tested were more active at lower pH and this effect was slightly more remarkable for peptides F6, F7, and F11, compared to F2 and F3. Formation of isolated colonies was observed inside the growth inhibitory zones induced by F2 and F3 but not inside those induced by F6, F7, and F11. The vast majority (98\%) of those colonies did not originate from truly resistant cells. The true resistance of 2\% of isolates was due to the impaired transport of di- and to a lower extent, tripeptides. The resistant cells did not exhibit a lower expression of \(PTR2\), \(PTR22\), or \(OPT1-3\) genes, but mutations in the \(PTR2\) gene resulting in T422H, A320S, D119V, and A320S substitutions in the amino acid sequence of Ptr2p were found.},
  language  = {en}
}
@article{WagenerLoiko2017,
  author    = {Wagener, Johannes and Loiko, Veronika},
  title     = {Recent insights into the paradoxical effect of echinocandins},
  series = {Journal of Fungi},
  volume    = {4},
  journal   = {Journal of Fungi},
  number    = {1},
  issn      = {2309-608X},
  doi       = {10.3390/jof4010005},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197960},
  pages     = {5},
  year      = {2017},
  abstract  = {Echinocandin antifungals represent one of the most important drug classes for the treatment of invasive fungal infections. The mode of action of the echinocandins relies on inhibition of the β-1,3-glucan synthase, an enzyme essentially required for the synthesis of the major fungal cell wall carbohydrate β-1,3-glucan. Depending on the species, echinocandins may exert fungicidal or fungistatic activity. Apparently independent of this differential activity, a surprising in vitro phenomenon called the "paradoxical effect" can be observed. The paradoxical effect is characterized by the ability of certain fungal isolates to reconstitute growth in the presence of higher echinocandin concentrations, while being fully susceptible at lower concentrations. The nature of the paradoxical effect is not fully understood and has been the focus of multiple studies in the last two decades. Here we concisely review the current literature and propose an updated model for the paradoxical effect, taking into account recent advances in the field.},
  language  = {en}
}
@article{HampeFriedmanEdgertonetal.2017,
  author    = {Hampe, Irene A. I. and Friedman, Justin and Edgerton, Mira and Morschh{\"a}user, Joachim},
  title     = {An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses},
  series = {PLoS Pathogens},
  volume    = {13},
  journal   = {PLoS Pathogens},
  number    = {9},
  doi       = {10.1371/journal.ppat.1006655},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158883},
  pages     = {e1006655},
  year      = {2017},
  abstract  = {The opportunistic fungal pathogen Candida albicans frequently produces genetically altered variants to adapt to environmental changes and new host niches in the course of its life-long association with the human host. Gain-of-function mutations in zinc cluster transcription factors, which result in the constitutive upregulation of their target genes, are a common cause of acquired resistance to the widely used antifungal drug fluconazole, especially during long-term therapy of oropharyngeal candidiasis. In this study, we investigated if C. albicans also can develop resistance to the antimicrobial peptide histatin 5, which is secreted in the saliva of humans to protect the oral mucosa from pathogenic microbes. As histatin 5 has been shown to be transported out of C. albicans cells by the Flu1 efflux pump, we screened a library of C. albicans strains that contain artificially activated forms of all zinc cluster transcription factors of this fungus for increased FLU1 expression. We found that a hyperactive Mrr1, which confers fluconazole resistance by upregulating the multidrug efflux pump MDR1 and other genes, also causes FLU1 overexpression. Similarly to the artificially activated Mrr1, naturally occurring gain-of-function mutations in this transcription factor also caused FLU1 upregulation and increased histatin 5 resistance. Surprisingly, however, Mrr1-mediated histatin 5 resistance was mainly caused by the upregulation of MDR1 instead of FLU1, revealing a previously unrecognized function of the Mdr1 efflux pump. Fluconazole-resistant clinical C. albicans isolates with different Mrr1 gain-of-function mutations were less efficiently killed by histatin 5, and this phenotype was reverted when MRR1 was deleted. Therefore, antimycotic therapy can promote the evolution of strains that, as a consequence of drug resistance mutations, simultaneously have acquired increased resistance against an innate host defense mechanism and are thereby better adapted to certain host niches.},
  language  = {en}
}
@article{MoussetBuchheidtHeinzetal.2014,
  author    = {Mousset, Sabine and Buchheidt, Dieter and Heinz, Werner and Ruhnke, Markus and Cornely, Oliver A. and Egerer, Gerlinde and Kr{\"u}ger, William and Link, Hartmut and Neumann, Silke and Ostermann, Helmut and Panse, Jens and Penack, Olaf and Rieger, Christina and Schmidt-Hieber, Martin and Silling, Gerda and S{\"u}dhoff, Thomas and Ullmann, Andrew J. and Wolf, Hans-Heinrich and Maschmeyer, Georg and B{\"o}hme, Angelika},
  title     = {Treatment of invasive fungal infections in cancer patients—updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)},
  series = {Annals of Hematology},
  volume    = {96},
  journal   = {Annals of Hematology},
  doi       = {10.1007/s00277-013-1867-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121340},
  pages     = {13-32},
  year      = {2014},
  abstract  = {Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection.},
  language  = {en}
}