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Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
letter
. 2017 Jun 27;61(7):e00435-17. doi: 10.1128/AAC.00435-17

In Vitro Activity of a Novel Glucan Synthase Inhibitor, SCY-078, against Clinical Isolates of Candida auris

Elizabeth L Berkow a,, David Angulo b, Shawn R Lockhart a
PMCID: PMC5487607  PMID: 28483955

LETTER

Candida auris, an emerging fungal pathogen that is associated with high mortality, has been identified in many countries across the world. It is often mistaken for other Candida species in the clinical laboratory and has shown a marked ability to withstand standard infection control practices. More troubling, C. auris can exhibit in vitro resistance to multiple antifungal agents—creating a challenge for clinicians directing treatment (13). As the emergence of this serious threat to public health continues, it will be important to evaluate the efficacy of novel antifungal agents as existing options may be inadequate.

SCY-078 is a triterpene glucan synthase inhibitor (GSI) that has been shown to exhibit both in vitro and in vivo activity against the most common Candida species, including echinocandin-resistant isolates (4). This compound differs from other GSIs (i.e., echinocandins) in that it is orally bioavailable. Additionally, unlike that of the echinocandins, the activity of this compound is not compromised by the most common mutations within the protein target Fks (5).

Here, we evaluate the in vitro susceptibility of SCY-078 against a collection of 100 isolates of the emerging pathogen Candida auris. Isolates represent each of the four known clades of C. auris and originate from countries all over the world, including India, Pakistan, Colombia, South Africa, and the United States (3). The collection includes isolates known to have elevated MICs against the echinocandins. All isolates were subjected to broth microdilution according to the standards of the Clinical and Laboratory Standards Institute reference methodology M27-A3 (6). Antifungal panels were read visually after 24 h of incubation for a 50% decrease in growth compared to a drug-free control.

The distribution of MIC values of SCY-078 ranged from 0.0625 μg/ml to 2 μg/ml (Table 1). The overall mode was 1 μg/ml, and the MIC50 and MIC90 were 0.5 μg/ml and 1 μg/ml, respectively. SCY-078 showed activity against all clades of C. auris with very little variation in activity between the clades. These data are consistent with what has been observed with other species of Candida (4, 7).

TABLE 1.

Distribution of MIC values

MIC 0.03 0.0625 0.125 0.25 0.5 1 2 4 8
No. of isolates 4 3 12 31 46 4

The distribution of MIC values among the collection for the echinocandins ranged from 0.03 to >8 μg/ml for micafungin, 0.03 to >16 μg/ml for caspofungin, and 0.125 to >16 μg/ml for anidulafungin. Among seven isolates with elevated MICs to one or more echinocandins, the MIC range of SCY-078 was 0.5 to 1 μg/ml with a MIC50 of 1 μg/ml (Table 2). For the sake of such a compact publication, we elected to display only those isolates which displayed echinocandin resistance in Table 2.

TABLE 2.

SCY-078 MIC data compared to isolates with elevated echinocandin MICs

Isolate MIC (μg/ml) of drug:
Anidulafungin Caspofungin Micafungin SCY-078
1 8 1 4 1
2 16 1 4 1
3 1 16 1 1
4 2 16 2 1
5 4 0.5 0.5 0.5
6 >16 >16 >8 0.5
7 4 >16 1 1

This report describes in vitro susceptibilities of a large collection of C. auris isolates to the novel glucan synthase inhibitor SCY-078 (7). This drug is the only β-1,3-glucan synthase inhibitor with both oral and intravenous formulations in development. While there are no interpretative breakpoints for C. auris against SCY-078, these MIC values are within the achievable serum level and indicate widespread activity (8). There are no significant differences among MIC values between the clades, indicating that any genetic diversity arising between geographically distinct isolates does not influence the activity of the compound. Furthermore, resistance to other β-1,3-glucan synthase inhibitors is not indicative of resistance to this compound. Echinocandin-resistant isolates exhibited MICs consistent with those of echinocandin-susceptible isolates. In conclusion, SCY-078 is a promising novel antifungal agent against Candida auris, and further investigation is warranted.

ACKNOWLEDGMENTS

We are grateful to the following members of the Mycotic Diseases Branch for their support: Lalitha Gade, Nancy Chow, Rory Welsh, Ana Litvintseva, Joyce Peterson, and Ngoc Le.

The findings and conclusions in this work are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

David Angulo is employed by SCYNEXIS, Inc., the manufacturer of SCY-078.

REFERENCES

  • 1.Chowdhary A, Voss A, Meis JF. 2016. Multidrug-resistant Candida auris: ‘new kid on the block’ in hospital-associated infections? J Hosp Infect 94:209–212. doi: 10.1016/j.jhin.2016.08.004. [DOI] [PubMed] [Google Scholar]
  • 2.Vallabhaneni S, Kallen A, Tsay S, Chow N, Welsh R, Kerins J, Kemble SK, Pacilli M, Black SR, Landon E, Ridgway J, Palmore TN, Zelzany A, Adams EH, Quinn M, Chaturvedi S, Greenko J, Fernandez R, Southwick K, Furuya EY, Calfee DP, Hamula C, Patel G, Barrett P, Lafaro P, Berkow EL, Moulton-Meissner H, Noble-Wang J, Fagan RP, Jackson BR, Lockhart SR, Litvintseva AP, Chiller TM. 2016. Investigation of the first seven reported cases of Candida auris, a globally emerging invasive, multidrug-resistant fungus—United States, May 2013-August 2016. MMWR Morb Mortal Wkly Rep 65:1234–1237. doi: 10.15585/mmwr.mm6544e1. [DOI] [PubMed] [Google Scholar]
  • 3.Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP, Colombo AL, Calvo B, Cuomo CA, Desjardins CA, Berkow EL, Castanheira M, Magobo RE, Jabeen K, Asghar RJ, Meis JF, Jackson B, Chiller T, Litvintseva AP. 2017. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 64:134–140. doi: 10.1093/cid/ciw691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Pfaller MA, Messer SA, Motyl MR, Jones RN, Castanheira M. 2013. Activity of MK-3118, a new oral glucan synthase inhibitor, tested against Candida spp. by two international methods (CLSI and EUCAST). J Antimicrob Chemother 68:858–863. doi: 10.1093/jac/dks466. [DOI] [PubMed] [Google Scholar]
  • 5.Jimenez-Ortigosa C, Paderu P, Motyl MR, Perlin DS. 2014. Enfumafungin derivative MK-3118 shows increased in vitro potency against clinical echinocandin-resistant Candida species and Aspergillus species isolates. Antimicrob Agents Chemother 58:1248–1251. doi: 10.1128/AAC.02145-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.CLSI. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard, 3rd ed CLSI document M27-A3. CLSI, Wayne, PA. [Google Scholar]
  • 7.Larkin E, Hager C, Chandra J, Mukherjee PK, Retuerto M, Salem I, Long L, Isham N, Kovanda L, Borroto-Esoda K, Wring S, Angulo D, Ghannoum M. 2017. The emerging pathogen Candida auris: growth phenotype, virulence factors, activity of antifungals, and effect of SCY-078, a novel glucan synthesis inhibitor, on growth morphology and biofilm formation. Antimicrob Agents Chemother 61:e02396-16. doi: 10.1128/AAC.02396-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Lepak AJ, Marchillo K, Andes DR. 2015. Pharmacodynamic target evaluation of a novel oral glucan synthase inhibitor, SCY-078 (MK-3118), using an in vivo murine invasive candidiasis model. Antimicrob Agents Chemother 59:1265–1272. doi: 10.1128/AAC.04445-14. [DOI] [PMC free article] [PubMed] [Google Scholar]

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