microorganisms Review Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris Muriel Billamboz 1,2,*, Zeeshan Fatima 3, Saif Hameed 3 and Samir Jawhara 4,* 1 Inserm, CHU Lille, Institut Pasteur Lille, Université Lille, U1167—RID-AGE—Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement, F-59000 Lille, France 2 Junia, Health and Environment, Laboratory of Sustainable Chemistry and Health, F-59000 Lille, France 3 Amity Institute of Biotechnology, Amity University Haryana, Manesar, Gurugram 122413, India; [email protected] (Z.F.); [email protected] (S.H.) 4 UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Centre National de la Recherche Scientifique, INSERM U1285, University of Lille, F-59000 Lille, France * Correspondence: [email protected] (M.B.); [email protected] (S.J.) 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. Citation: Billamboz, M.; Fatima, Z.; Keywords: Candida auris; antifungal drugs; repurposed drugs; combinatorial therapy; natural Hameed, S.; Jawhara, S. Promising compounds; nanoparticles Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris. Microorganisms 2021, 9, 634. https://doi.org/10.3390/ microorganisms9030634 1. Introduction First identified in 2009 from the ear canal of a patient in Japan [1], C. auris is now recog- Academic Editor: Eric Dannaoui nized as an emerging species of concern [2,3], and more and more publications are related to C. auris studies (Figure1). When searching for “ Candida auris” key words on Scifinder, Received: 25 January 2021 fewer than 1000 reports have been compiled, most of them during the two last years, Accepted: 8 March 2021 proving the acceleration of research and clinical studies around this emerging pathogen. Published: 18 March 2021 Its emergence is defined by the occurrence of C. auris infections in a dozen of countries all around the world. In Europe, since 2015, sporadic epidemics have been reported in Publisher’s Note: MDPI stays neutral Spain [4], United-Kingdom [5], Germany, or Norway [6], for example. Simultaneously, with regard to jurisdictional claims in candidiasis caused by C. auris were reported in Korea [7], South Korea [8], India [9–11], published maps and institutional affil- South-Africa [12], or Kowait [13]. In the same period, the United States were also af- iations. fected [14–16]. This human pathogen is associated with severe invasive infections with high mortality rates ranging from 35 to 72% [8,12,17,18]. Since June 2016, governmental in- stitutions (Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), World Health Organization (WHO), Pan American Health Copyright: © 2021 by the authors. Organization (PAHO), National institute for Communicable Diseases (NICD) ... ) have Licensee MDPI, Basel, Switzerland. issued clinical alerts to health care facilities and provided interim guidelines for clinical This article is an open access article management, laboratory testing and infection control of C. auris [19,20]. This fungus poses distributed under the terms and significant challenges to microbiologists and clinicians because of its frequent multidrug conditions of the Creative Commons resistance; high transmissibility and severe outcomes coupled with misidentification by Attribution (CC BY) license (https:// standard biochemical identification systems such as Vitek 2 [21]. creativecommons.org/licenses/by/ 4.0/). Microorganisms 2021, 9, 634. https://doi.org/10.3390/microorganisms9030634 https://www.mdpi.com/journal/microorganisms Microorganisms 2021, 9, 634 2 of 40 Microorganisms 2021, 9, x 2 of 42 350 300 250 200 year 150 100 Number of publications per of publications Number 50 0 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 FigureFigure 1.1. Evolution of of annual annual reports reports dealing dealing with with C.C. auris auris studiesstudies (Scifinder (Scifinder search, search, keykey word word Candida auris, Data Compiled on 31 December 2020). Candida auris, Data Compiled on 31 December 2020). Moreover,Moreover, the the widespread widespread and and prolonged prolonged use use of of available available antifungal antifungal drugs drugs has has given given riserise to to multidrug multidrug resistance resistance that that alters alters the therapeuticthe therapeutic available available options. opti Itons. has It been has reported been re- thatported nearly that 90% nearly of C .90%auris ofisolates C. auris exhibit isolates resistance exhibit resistance to fluconazole, to fluconazole, around 30% around resistance 30% toresistance amphotericin to amphotericin B, and less B, thanand less 5% than resistance 5% resistance to echinocandins to echinocandins [22,23]. [22,23]. Under Under such compellingsuch compelling circumstances, circumstances,C. auris C. displaysauris displays all the all features the features of a “superbug”of a “superbug” and effortsand ef- areforts ongoing are ongoing to identify to identify newtherapeutic new therapeutic alternatives alternatives to fight to againstfight againstC. auris C. infections.auris infec- Aftertions. introducing After introducingC. auris C.genomic auris genomic epidemiology epidemiology and virulence and viru factors,lence thisfactors, review this aims review at compilingaims at compiling the different the strategiesdifferent strategies and results and obtained results during obtained the pastduring ten the years past in ten the fieldyears ofin antifungal the field of research antifungal against research emerging againstC. emerging auris from C. a medicinalauris from chemista medicinal point chemist of view. point To summarize,of view. To summarize, six complementary six complementary strategies have strate beengies developed, have been developed, from the most from attractive the most toattractive the less reported:to the less (i) reported: repurposing (i) repurposin of drugs;g (ii) of evaluation drugs; (ii) ofevaluation combination of combination drugs; (iii) discoverydrugs; (iii) of discovery new drug-candidates; of new drug-candidates; (iv) traditional (iv) traditional medicines medicines and natural andcompounds; natural com- (v)pounds; metal, (v) metalloids metal, metalloids and complexes; and complexes; (vi) others (vi) approaches others approaches including including nanoparticles nanopar- and irradiation.ticles and irradiation. Results and Results data will and be data analyzed will be from analyzed a chemical from approach a chemical based approach on chemical based featureson chemical and physicochemicalfeatures and physicochemical descriptors suchdescriptors as lipophilicity such as lipophilicity (expressed by(expressed logP) and by topologicallogP) and polartopological surface polar area (TPSA)surface inarea order (TPSA) to establish in order a comparison to establish between a comparison classes be- of compoundstween classes and of definecompounds potential and common define potential pharmacophoric common moieties.pharmacophoric moieties. 2.2.Candida Candida aurisaurisGenomic Genomic Epidemiology Epidemiology and and Virulence Virulence Factors Factors 2.1. Global View 2.1. Global View C. auris is taxonomically placed as a close relative to the Candida haemulonii since its C. auris is taxonomically placed as a close relative to the Candida haemulonii since its discovery in 2009 from the ear canal of a patient in Japan [1]. C. auris was isolated in all discovery in 2009 from the ear canal of a patient in Japan [1]. C. auris was isolated in all continents except Antarctica. Munoz et al. found that four of the five clades of C. auris are continents except Antarctica. Munoz et al. found that four of the five clades of C. auris are genetically related to other Candida species including C. haemulonii, C. duobushaemulonii, genetically related to other Candida species including C. haemulonii, C. duobushaemulonii, and C. psuedohaemulonii [24]. These five genetically distinct clades of C. auris correspond to: Cladeand C. I frompsuedohaemulonii India and Pakistan [24]. These (South five Asian), genetically Clade distinct II from Japanclades (Eastof C. Asian),auris correspond Clade III fromto: Clade South I from Africa India (African), and Pakistan Clade IV (South from VenezuelaAsian), Clade (South II from American) Japan (East and most Asian), recently Clade aIII potential from South Clade Africa V from (African), Iran [22 Clade,25]. OverIV from the Venezuela past ten years, (SouthC. Am auriserican)has been and isolatedmost re- acrosscently all a majorpotential continents, Clade V including from Iran elsewhere [22,25]. Over in Asia, the Africa, past ten North years, and C. South