Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

Abstract

Invasive fungal infections represent an expanding threat to public health. During the past decade, a paradigm shift of candidiasis from Candida albicans to non-albicans Candida species has fundamentally increased with the advent of Candida auris. C. auris was identified in 2009 and is now recognized as an emerging species of concern and underscores the urgent need for novel drug development strategies. In this review, we discuss the genomic epidemiology and the main virulence factors of C. auris. We also focus on the different new strategies and results obtained during the past decade in the field of antifungal design against this emerging C. auris pathogen yeast, based on a medicinal chemist point of view. Critical analyses of chemical features and physicochemical descriptors will be carried out along with the description of reported strategies.

Keywords: Candida auris; antifungal drugs; combinatorial therapy; nanoparticles; natural compounds; repurposed drugs.

Figure 1

Evolution of annual reports dealing with C. auris studies (Scifinder search, key word Candida auris, Data Compiled on 31 December 2020).

Figure 2

Schematic overview of C. auris virulence factors. Stress resistance, hydrolytic enzyme production, thermotolerance, biofilm/adhesion to host cells, osmotolerance, filamentation, and white and opaque switching are important virulence traits in C. auris.

Figure 3

Structures of ebselen and alexidine dichloride.

Figure 4

Structures of iodoquinol, miltefosine, sertraline, taurolidine, octenidine dihydrochloride and bensulfuron methyl.

Figure 5

Proposed scaffold of reported C. auris antifungals.

Figure 6

Critical analysis for the guanidine derivatives.

Figure 7

Critical analysis for repurposing drugs.

Figure 8

Structure of Pivastatin and Sulfamethoxazole.

Figure 9

Structure of Colistin, Lopinavir and Aprepitant.

Figure 10

Oxadiazole-containing macrocylic peptides and azoffluxin.

Figure 11

Stilbene compounds tested by Seelem et al. in combination with itraconazole.

Figure 12

Series of derivatives from niclosamide and their activities towards growth and filamentation as reported by Selam et al.

Figure 13

CSA steroids as patented by Genberg, Beus and Savage and MYC-053 as reported by Tetz.

Figure 14

Rational design of cuminaldehyde-azole hybrid compounds by Soliman et al.

Figure 15

Structure of the derivatives of mefloquine as reported by Montoya et al.

Figure 16

Structures of OXA compounds described by Seleem, Mayhoub et al.

Figure 17

Series of pyrazolo[5,1-c][1,2,4]triazines described by Seleem et al.

Scheme 1

Synthesis of 2-aryloxazoline derivatives (ArOx) and the two most potent compounds ArOX-1 and ArOx-2.

Scheme 2

α-Iodonitroalkenes synthesis.

Scheme 3

Series of fluorinated hydrazone derivatives (FAH) as reported by Watt and Garneau-Tsodikova.

Figure 18

Structure of T-2307 and SCY-078 as reported by Patterson et al. and Larkin et al., respectively. Structure evolution of second generation fungerp SCY-247.

Scheme 4

Structure of prodrug APX001 and active moiety APX001A.

Scheme 5

Structure of gepinacin and modulations.

Figure 19

Modifications around the phenylthiazole compounds as reported by Seleem et al.

Figure 20

Structures of VT-1598 and PC945.

Figure 21

Structure of CD101.

Figure 22

Structure of selvamycin derivatives.

Scheme 6

Synthesis of CE-MP as reported by Chauhan and Loonker.

Figure 23

Structures of farnesol, [6]-shogoal and (−)-drimenol.

Figure 24

Composition of the five most common traditional herbal monomers as stated by Liu et al.

Figure 25

Structure of turbinmicin.

Figure 26

Structures of selected ceragenins CSAs.

Figure 27

Gol(I)-complexes as antifungals: structure, MIC values range and cytotoxicity.