Transport deficiency is the molecular basis of Candida albicans resistance to antifungal oligopeptides
Abstract
(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 mg/L 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.
Citations
-
7
CrossRef
-
0
Web of Science
-
6
Scopus
Authors (8)
Cite as
Full text
- Publication version
- Accepted or Published Version
- License
- open in new tab
Keywords
Details
- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
-
Frontiers in Microbiology
no. 8,
ISSN: 1664-302X - Language:
- English
- Publication year:
- 2017
- Bibliographic description:
- Schielmann M., Szweda P., Gucwa K. M., Kawczyński M., Milewska M. J., Martynow D., Morschhauser J., Milewski S.: Transport deficiency is the molecular basis of Candida albicans resistance to antifungal oligopeptides// Frontiers in Microbiology. -Vol. 8, (2017), s.2154-
- DOI:
- Digital Object Identifier (open in new tab) 10.3389/fmicb.2017.02154
- Bibliography: test
-
- Ames, B. N., Ames, G. F. L., and Young, Y. D. (1973). Illicit transport: the oligopeptide permease. Proc. Natl. Acad. Sci. U.S.A. 70, 456-458. doi: 10.1073/ pnas.70.2.456 open in new tab
- Andruszkiewicz, R., Chmara, H., Milewski, S., and Borowski, E. (1986). Synthesis of N 3 -fumaramoyl-L-2,3-diaminopropanoic acid analogues, the irreversible inhibitors of glucosamine synthetase. Int. J. Pept. Protein Res. 27, 449-453. doi: 10.1111/j.1399-3011.1986.tb01041.x open in new tab
- Andruszkiewicz, R., Chmara, H., Milewski, S., and Borowski, E. (1987). Synthesis and biological properties of N 3 -(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid dipeptides, a novel group of antimicrobial agents. J. Med. Chem. 30, 1715-1719. doi: 10.1021/jm00393a005 open in new tab
- Andruszkiewicz, R., Milewski, S., Zieniawa, T., and Borowski, E. (1990). Anticandidal properties of N 3 -(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid oligopeptides. J. Med. Chem. 33, 132-135. doi: 10.1021/jm0016 3a022 open in new tab
- Basrai, M. A., Lubkowitz, M. A., Perry, J. R., Miller, D., Krainer, E., Naider, F., et al. (1995). Cloning of a Candida albicans peptide transport gene. Microbiology 141, 1147-1156. doi: 10.1099/13500872-141-5-1147 open in new tab
- Basrai, M. A., Zhang, H. L., Miller, D., Naider, F., and Becker, J. M. (1992). Toxicity of oxalysine and oxalysine-containing peptides against Candida albicans: regulation of peptide transport by amino acids. Microbiology 138, 2353-2362. doi: 10.1099/00221287-138-11-2353 open in new tab
- Braun, B. R., van Het Hoog, M., d'Enfert, C., Martchenko, M., Dungan, J., Kuo, A., et al. (2005). A human-curated annotation of the Candida albicans genome. PLOS Genet. 1, 36-57. doi: 10.1371/journal.pgen. 0010001 open in new tab
- Clinical Laboratory Standards Institute (2008). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, 3rd Edn. Wayne, PA: Clinical Laboratory Standards Institute. open in new tab
- Dabas, N., and Morschhäuser, J. (2008). A transcription factor regulatory cascade controls secreted aspartic protease expression in Candida albicans. Mol. Microbiol. 69, 586-602. doi: 10.1111/j.1365-2958.2008.06297.x open in new tab
- Desai, P. R., Thakur, A., Ganguli, D., Paul, S., Morschhäuser, J., and Bachhawat, A. K. (2011). Glutathione utilization by Candida albicans member of the oligopeptide transporter family. J. Biol. Chem. 286, 41183-41194. doi: 10.1074/ jbc.M111.272377 open in new tab
- Doi, E., Shibata, D., and Matoba, T. (1981). Modified colorimetric ninhydrin method for peptidase assay. Anal. Biochem. 118, 173-184. doi: 10.1016/0003- 2697(81)90175-5 open in new tab
- Dunkel, N., Hertlein, T., Franz, R., Reuß, O., Sasse, C., Schäfer, T., et al. (2013). Roles of different peptide transporters in nutrient acquisition in Candida albicans. Eukaryot. Cell 12, 520-528. doi: 10.1128/EC.00008-13 open in new tab
- Gillum, A. M., Tsay, E. Y., and Kirsch, D. R. (1984). Isolation of the Candida albicans gene for orotidine-5'-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations. Mol. Gen. Genet. 198, 179-182. doi: 10.1007/BF00328721 open in new tab
- Gomez, J. A., Chen, J., Ngo, J., Hajkova, D., Yeh, I. J., Gama, V., et al. (2010). Cell- penetrating penta-peptides (CPP5s): measurement of cell entry and protein- transduction activity. Pharmaceuticals 3, 3594-3613. doi: 10.3390/ph312 open in new tab
- Hori, M., Eguchi, J., Kakiki, K., and Misato, T. (1974). Studies on the mode of action of polyoxins. VI. Effect of polyoxin B on chitin synthesis in polyoxin- sensitive and resistant strains of Alternaria kikuchiana. J. Antibiot. 27, 260-266. doi: 10.7164/antibiotics.27.260 open in new tab
- Island, M. D., Naider, F., and Becker, J. M. (1987). Regulation of dipeptide transport in Saccharomyces cerevisiae by micromolar amino acid concentrations. J. Bacteriol. 169, 2132-2136. doi: 10.1128/jb.169.5.2132-2136. 1987 open in new tab
- Kenig, M., and Abraham, E. P. (1976). Antimicrobial activities and antagonists of bacilysin and anticapsin. J. Gen. Microbiol. 94, 37-45. doi: 10.1099/00221287- 94-1-37 open in new tab
- Kingsbury, W. D., Boehm, J. C., and Mehta, R. J. (1983). Transport of antimicrobial agents using peptide carrier systems: anticandidal activity of m-fluorophenylalanine-peptide conjugates. J. Med. Chem. 26, 1725-1729. doi: 10.1021/jm00366a013 open in new tab
- Kryński, S., and Becla, E. (1963). Bacteriology of tetaine. Acta Microbiol. Polon. 12, 131-142. open in new tab
- Lichliter, W. D., Naider, F., and Becker, J. M. (1976). Basis for the design of anticandidal agents from studies of peptide utilization in Candida albicans. Antimicrob. Agents Chemother. 10, 483-490. doi: 10.1128/AAC.10. 3.483 open in new tab
- Livak, K. J., and Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2 − CT method. Methods 25, 402-408. doi: 10.1006/meth.2001.1262 open in new tab
- Lopez-Garcia, B., Ubhayasekera, W., Gallo, R. L., and Marcos, J. F. (2007). Parallel evaluation of antimicrobial peptides derived from the synthetic PAF26 and the human LL37. Biochem. Biophys. Res. Commun. 356, 107-113. doi: 10.1016/j. bbrc.2007.02.093 open in new tab
- Martinez, P., and Ljungdahl, P. O. (2005). Divergence of Stp1 and Stp2 transcription factors in Candida albicans places virulence factors required for proper nutrient acquisition under amino acid control. Mol. Cell Biol. 25, 9435-9446. doi: 10.1128/MCB.25.21.9435-9446.2005 open in new tab
- McCarthy, P. J., Newman, D. J., Nisbet, L. J., and Kingsbury, W. D. (1985). Relative rates of transport of peptidyl drugs by Candida albicans. Antimicrob. Agents Chemother. 28, 494-499. doi: 10.1128/AAC.28.4.494 open in new tab
- Mehta, R. J., Kingsbury, W. D., Valenta, J., and Actor, P. (1984). Anti-Candida activity of polyoxin: example of peptide transport in yeasts. Antimicrob. Agents Chemother. 25, 373-374. doi: 10.1128/AAC.25.3.373 open in new tab
- Milewski, S., Andruszkiewicz, R., and Borowski, E. (1988). Substrate specificity of peptide permeases in Candida albicans. FEMS Microbiol. Lett. 50, 73-78. doi: 10.1111/j.1574-6968.1988.tb02914.x open in new tab
- Milewski, S., Andruszkiewicz, R., Kasprzak, L., Mazerski, J., Mignini, F., and Borowski, E. (1991). Mechanism of action of anticandidal dipeptides containing inhibitors of glucosamine-6-phosphate synthase. Antimicrob. Agents Chemother. 35, 36-43. doi: 10.1128/AAC.35.1.36 open in new tab
- Moriyama, B., Gordon, L. A., McCarthy, M., Henning, S. A., Walsh, T. J., and Penzak, S. R. (2014). Emerging drugs and vaccines for Candidemia. Mycoses 57, 718-733. doi: 10.1111/myc.12265 open in new tab
- Morschhäuser, J. (2011). Nitrogen regulation of morphogenesis and protease secretion in Candida albicans. Int. J. Med. Microbiol. 301, 390-394. doi: 10.1016/ j.ijmm.2011.04.005 open in new tab
- Ramsey, J. D., and Flynn, N. H. (2015). Cell-penetrating peptides transport therapeutics into cells. Pharmacol. Ther. 154, 78-86. doi: 10.1016/j.pharmthera. 2015.07.003 open in new tab
- Rapp, C., Jung, G., Kugler, M., and Loeffler, W. (1988). Rhizocticins -new phosphono-oligopeptides with antifungal activity. Justus Liebigs Ann. Chem. 1988, 655-661. doi: 10.1002/jlac.198819880707 open in new tab
- Reuß, O., and Morschhäuser, J. (2006). A family of oligopeptide transporters is required for growth of Candida albicans on proteins. Mol. Microbiol. 60, 795-812. doi: 10.1111/j.1365-2958.2006.05136.x open in new tab
- Reuß, O., Vik, A., Kolter, R., and Morschhäuser, J. (2004). The SAT1 flipper, an optimized tool for gene disruption in Candida albicans. Gene 341, 119-127. doi: 10.1016/j.gene.2004.06.021 open in new tab
- Sanguinetti, M., Posteraro, B., and Lass-Flörl, C. (2015). Antifungal drug resistance among Candida species: mechanisms and clinical impact. Mycoses 58(Suppl. 2), 2-13. doi: 10.1111/myc.12330 open in new tab
- Semlali, A., Leungb, K. P., Curta, S., and Rouabhia, M. (2011). Antimicrobial decapeptide KSL-W attenuates Candida albicans virulence by modulating its effects on Toll-like receptor, human β-defensin, and cytokine expression by engineered human oral mucosa. Peptides 32, 859-867. doi: 10.1016/j.peptides. 2011.01.020 open in new tab
- Skwarecki, A. S., Milewski, S., Schielmann, M., and Milewska, M. J. (2016). Antimicrobial molecular nanocarrier-drug conjugates. Nanomedicine 12, 2215-2240. doi: 10.1016/j.nano.2016.06.002 open in new tab
- Staib, F. (1965). Serum-proteins as nitrogen source for yeastlike fungi. Sabouraudia 4, 187-193. doi: 10.1080/00362176685190421 open in new tab
- Theberge, S., Semlali, A., Alamri, A., Leung, K. P., and Rouabhia, M. (2013). open in new tab
- C. albicans growth, transition, biofilm formation, and gene expression modulation by antimicrobial decapeptide KSL-W. BMC Microbiol. 13:246. doi: 10.1186/1471-2180-13-246 open in new tab
- Ti, J. S., Steinfeld, A. S., Naider, F., Gulumoglu, A., Lewis, S. V., and Becker, J. M. (1980). Anticandidal activity of pyrimidine-peptide conjugates. J. Med. Chem. 23, 913-918. doi: 10.1021/jm00182a019 open in new tab
- Wakieć, R., Gabriel, I., Prasad, R., Becker, J. M., Payne, J. W., and Milewski, S. (2008). Enhanced susceptibility to antifungal oligopeptides in yeast strains overexpressing ABC multidrug efflux pumps. Antimicrob. Agents Chemother. 52, 4057-4063. doi: 10.1128/AAC.01648-07 open in new tab
- Xia, Z., Turner, G. C., Hwang, C.-S., Byrd, C., and Varshavsky, A. (2008). Amino acids induce peptide uptake via accelerated degradation of CUP9, the transcriptional repressor of the PTR2 peptide transporter. J. Biol. Chem. 283, 28958-28968. doi: 10.1074/jbc.M803980200 open in new tab
- Yadan, J. C., Gonneau, M., Sarthou, P., and Le Goffic, F. (1984). Sensitivity to nikkomycin Z in Candida albicans: role of peptide permeases. J. Bacteriol. 160, 884-888. open in new tab
- Verified by:
- Gdańsk University of Technology
seen 144 times