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The Neosartorya Fischeri Antifungal Protein 2 (NFAP2) International Journal of Molecular Sciences Article The Neosartorya fischeri Antifungal Protein 2 (NFAP2): A New Potential Weapon against Multidrug-Resistant Candida auris Biofilms Renátó Kovács 1,2,3,* , Fruzsina Nagy 1,4, Zoltán Tóth 1,4,5, Lajos Forgács 1,4, Liliána Tóth 6,7, Györgyi Váradi 8, Gábor K. Tóth 8,9, Karina Vadászi 1, Andrew M. Borman 10,11 ,László Majoros 1 and László Galgóczy 6,7 1 Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary; [email protected] (F.N.); [email protected] (Z.T.); [email protected] (L.F.); [email protected] (K.V.); [email protected] (L.M.) 2 Faculty of Pharmacy, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary 3 Department of Metagenomics, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary 4 Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary 5 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary 6 Institute of Plant Biology, Biological Research Centre, Temesvári krt. 62, 6726 Szeged, Hungary; [email protected] (L.T.); [email protected] (L.G.) 7 Department of Biotechnology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, 6726 Szeged, Hungary 8 Department of Medical Chemistry, Faculty of Medicine, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary; [email protected] (G.V.); [email protected] (G.K.T.) 9 MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary 10 UK National Mycology Reference Laboratory, Public Health England, Science Quarter, Southmead Hospital, Bristol BS10 5NB, UK; [email protected] 11 Citation: Kovács, R.; Nagy, F.; Medical Research Council Centre for Medical Mycology (MRC CMM), University of Exeter, Tóth, Z.; Forgács, L.; Tóth, L.; Exeter EX4 4QD, UK Váradi, G.; Tóth, G.K.; Vadászi, K.; * Correspondence: [email protected]; Tel.: +36-52-255-425 Borman, A.M.; Majoros, L.; et al. The Neosartorya fischeri Antifungal Protein Abstract: Candida auris is a potential multidrug-resistant pathogen able to persist on indwelling 2 (NFAP2): A New Potential Weapon devices as a biofilm, which serve as a source of catheter-associated infections. Neosartorya fischeri against Multidrug-Resistant Candida antifungal protein 2 (NFAP2) is a cysteine-rich, cationic protein with potent anti-Candida activity. We auris Biofilms. Int. J. Mol. Sci. 2021, 22, studied the in vitro activity of NFAP2 alone and in combination with fluconazole, amphotericin B, 771. https://doi.org/10.3390/ijms anidulafungin, caspofungin, and micafungin against C. auris biofilms. The nature of interactions 22020771 was assessed utilizing the fractional inhibitory concentration index (FICI), a Bliss independence model, and LIVE/DEAD viability assay. NFAP2 exerted synergy with all tested antifungals with Received: 30 November 2020 FICIs ranging between 0.312–0.5, 0.155–0.5, 0.037–0.375, 0.064–0.375, and 0.064–0.375 for flucona- Accepted: 11 January 2021 zole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. These results were Published: 14 January 2021 confirmed using a Bliss model, where NFAP2 produced 17.54 µM2%, 2.16 µM2%, 33.31 µM2%, 10.72 µM2%, and 111.19 µM2% cumulative synergy log volume in combination with fluconazole, am- Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- photericin B, anidulafungin, caspofungin, and micafungin, respectively. In addition, biofilms exposed ms in published maps and institutio- to echinocandins (32 mg/L) showed significant cell death in the presence of NFAP2 (128 mg/L). Our nal affiliations. study shows that NFAP2 displays strong potential as a novel antifungal compound in alternative therapies to combat C. auris biofilms. Keywords: antifungal lock therapy; Candida auris; biofilm; NFAP2; drug–drug interaction; antifungal Copyright: © 2021 by the authors. Li- susceptibility testing censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- 1. Introduction tribution (CC BY) license (https:// creativecommons.org/licenses/by/ Candida auris is the first fungal pathogen to be announced as a global public health 4.0/). threat due to its ability to spread from patient-to-patient and cause invasive infections Int. J. Mol. Sci. 2021, 22, 771. https://doi.org/10.3390/ijms22020771 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 771 2 of 14 with high mortality [1–3]. Although, the majority of C. auris isolates have been recovered from patients with candidemia; several cases have also been observed from catheter- associated infections because C. auris shows a potent capacity to develop biofilms on medical devices [4–6]. Clinical surveys indicated that catheters were the predominant source of infection in 89% of C. auris candidaemia cases while this ratio was only 46% in non-C. auris bloodstream infections [7,8]. Recently, it was reported that nearly 40% of clinical C. auris isolates exhibit a multidrug-resistant phenotype, which is more pronounced in sessile communities. In addition, the ratio of pan-resistant isolates to all three commonly prescribed antifungal drugs is increasing in multiple countries [9,10]. In the last decade, alternative antifungal strategies, such as antifungal lock therapy- has received more attention as an alternative salvage therapy to eradicate intraluminal Candida biofilms [11,12]. To date, there is no officially approved antifungal lock strategy, such an approach would be particularly important in certain populations, such as patients with coagulopathies [13]. Echinocandins are promising targets for several potential lock solutions; however, the minimum inhibitory concentration (MIC90) values of C. auris biofilms ranged from 0.25 to >32 mg/L for caspofungin and micafungin, which represents a 2- to >512-fold increase in resistance when compared to planktonic cells, a difference that is likely to negatively impact clinical outcome [10,14]. A new potential lock strategy may be the antifungal protein-based lock solution against C. auris biofilms; although, to date, there are no data regarding the susceptibility of C. auris biofilms to antifungal proteins. Neosartorya fischeri antifungal protein 2 (NFAP2) is a novel member of small cysteine-rich and cationic antifungal proteins from filamentous ascomycetes (crAFPs) [15]. Previous studies demonstrated that this protein has a potential applicability in the treatment of Candida infections. NFAP2 inhibited the growth of clinically relevant Candida species. Furthermore, it interacted synergistically in combination with fluconazole against planktonic and sessile C. albicans cells in vitro and in vivo [16,17]. In light of these promising findings, the present study aimed to examine the in vitro efficacy of NFAP2 alone and in combination with traditional antifungal agents against C. auris biofilms to evaluate a new potential therapeutic approach against this fungal superbug. 2. Results 2.1. In Vitro Susceptibility of Planktonic Cells The median MICs against planktonic C. auris cells (pMIC) ranged from 4 to > 32 mg/L, 0.25 to 1 mg/L, 0.06 to 0.5 mg/L, 0.5 to 1 mg/L, and 0.12 to 2 mg/L for fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. The median pMIC to fluconazole of strains 12 and 27 was 4 mg/L, which correspond to the susceptible tentative breakpoint; while isolates 10, 20, and 82 were considered fluconazole-resistant based on the tentative MIC breakpoints recommended by the Centers for Disease Control and Prevention (≥32 mg/L for fluconazole) [18]. Regarding amphotericin B and the tested echinocandins, all isolates were susceptible according to tentative MIC breakpoints (≥2 mg/L for amphotericin B, ≥4 mg/L for anidulafungin, ≥2 mg/L for caspofungin, and ≥4 mg/L for micafungin) [18]. The median pMICs for NFAP2 ranged from 32 to 512 mg/L. 2.2. In Vitro Susceptibility of Sessile Biofilm Cells The MIC results (medians and ranges) on C. auris biofilms (sMIC) are shown in Table1 . Most of the isolates in biofilm form proved to be resistant to fluconazole, anidulafungin, caspofungin, micafungin, and NFAP2; while amphotericin B effectively inhibited the via- bility of sessile C. auris cells (sMIC: 1–2 mg/L) (Table1). The median sMICs observed for fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin in combination with NFAP2 were reduced by 32- to 128-fold, 4- to 64-fold, 16- to 128-fold, 4- to 128-fold, and 64- to 128-fold, respectively (Table1). The median sMICs for NFAP2 exhibited a 2- to 4-fold, 4- to 128-fold, 8- to 128-fold, 8- to 16-fold, and 4- to 256-fold decrease combined with fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively (Table1). These results indicated that the combinatorial application of the tested conven- Int. J. Mol. Sci. 2021, 22, 771 3 of 14 tional antifungal agents with NFAP2 results in a significant reduction in the viability of sessile cells. Table 1. Sessile minimum inhibitory concentrations (sMICs) of fluconazole (FLU), amphotericin B (AMB), anidulafungin (ANI), caspofungin (CAS) and micafungin (MICA) alone and in combination with NFAP2 against C. auris biofilms. Median MIC (Range) of Drug Used (50% OD492 Reduction in Metabolic Activity) Drug Isolate Alone In Combination Drug (mg/L) NFAP2 (mg/L) Drug (mg/L) NFAP2
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