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. 2017 Nov 7:8:2154.
doi: 10.3389/fmicb.2017.02154. eCollection 2017.

Transport Deficiency Is the Molecular Basis of Candida albicans Resistance to Antifungal Oligopeptides

Marta Schielmann  1 , Piotr Szweda  1 , Katarzyna Gucwa  1 , Marcin Kawczyński  2 , Maria J Milewska  2 , Dorota Martynow  1 , Joachim Morschhäuser  3 , Sławomir Milewski  1
Affiliations

Transport Deficiency Is the Molecular Basis of Candida albicans Resistance to Antifungal Oligopeptides

Marta Schielmann et al. Front Microbiol. .

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.

Keywords: Candida albicans; antifungals; oligopeptides; permease; resistance mechanism.

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Figures

FIGURE 1
FIGURE 1
pH dependence of MIC values of FMDP-oligopeptides. MICs were determined against C. albicans SC 5314. (A) RPMI-1640 buffered with MOPS. (B) YNB-SG buffered with MOPS.
FIGURE 2
FIGURE 2
Morphological changes induced in C. albicans SC 5314 cells upon action of F11. Cells were stained with Calcofluor White for chitin. (A) Control—untreated cells. (B) Cells treated with F11, 100 μg mL-1.
FIGURE 3
FIGURE 3
Disc diffusion activity determination of FMDP-oligopeptides. YNB-AS agar medium, 10 μg of each peptide applied on a disc. (A) F2; (B) F3; (C) F6; (D) F7; (E) F11.
FIGURE 4
FIGURE 4
Uptake rates of FMDP-oligopeptides and model alanyl peptides to isolates resistant to F2/F3. (A) Dipeptides. (B) Tripeptides. (C) (Ala)4 and F6.
See this image and copyright information in PMC

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