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Cell Wall-Modifying Antifungal Drugs

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The Fungal Cell Wall

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 425))

Abstract

Antifungal therapy is a critical component of patient management for invasive fungal diseases. Yet, therapeutic choices are limited as only a few drug classes are available to treat systemic disease, and some infecting strains are resistant to one or more drug classes. The ideal antifungal inhibits a fungal-specific essential target not present in human cells to avoid off-target toxicities. The fungal cell wall is an ideal drug target because its integrity is critical to cell survival and a majority of biosynthetic enzymes and wall components is unique to fungi. Among currently approved antifungal agents and those in clinical development, drugs targeting biosynthetic enzymes of the cell wall show safe and efficacious antifungal properties, which validates the cell wall as a target. The echinocandins, which inhibit β-1,3-glucan synthase, are recommended as first-line therapy for Candida infections. Newer cell wall-active drugs in clinical development encompass next-generation glucan synthase inhibitors including a novel echinocandin and an enfumafungin, an inhibitor of Gwt1, a key component of GPI anchor protein biosynthesis, and a classic inhibitor of chitin biosynthesis. As the cell wall is rich in potential drug discovery targets, it is primed to help deliver the next generation of antifungal drugs.

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References

  • Alexander BD, Johnson MD, Pfeiffer CD, Jimenez-Ortigosa C, Catania J, Booker R, Castanheira M, Messer SA, Perlin DS, Pfaller MA (2013) Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 56(12):1724–1732

    PubMed  PubMed Central  Google Scholar 

  • Arendrup MC, Perlin DS (2014) Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis 27(6):484–492

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arendrup MC, Chowdhary A, Astvad KMT, Jorgensen KM (2018a) APX001A In vitro activity against contemporary blood isolates and Candida auris determined by the EUCAST reference method. Antimicrob Agents Chemother 62(10)

    Google Scholar 

  • Arendrup MC, Meletiadis J, Zaragoza O, Jorgensen KM, Marcos-Zambrano LJ, Kanioura L, Cuenca-Estrella M, Mouton JW, Guinea J (2018b) Multicentre determination of rezafungin (CD101) susceptibility of Candida species by the EUCAST method. Clin Microbiol Infect 24(11):1200–1204

    CAS  PubMed  Google Scholar 

  • Bachmann SP, VandeWalle K, Ramage G, Patterson TF, Wickes BL, Graybill JR, Lopez-Ribot JL (2002) In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob Agents Chemother 46(11):3591–3596

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bader JC, Lakota EA, Flanagan S, Ong V, Sandison T, Rubino CM, Bhavnani SM, Ambrose PG (2018) Overcoming the resistance hurdle: pharmacokinetic-pharmacodynamic target attainment analyses for rezafungin (CD101) against Candida albicans and Candida glabrata. Antimicrob Agents Chemother 62(6)

    Google Scholar 

  • Bartizal K, Abruzzo G, Trainor C, Krupa D, Nollstadt K, Schmatz D, Schwartz R, Hammond M, Balkovec J, Vanmiddlesworth F (1992) In vitro antifungal activities and in vivo efficacies of 1,3-beta-d-glucan synthesis inhibitors L-671,329, L-646,991, tetrahydroechinocandin B, and L-687,781, a papulacandin. Antimicrob Agents Chemother 36(8):1648–1657

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bartizal K, Gill CJ, Abruzzo GK, Flattery AM, Kong L, Scott PM, Smith JG, Leighton CE, Bouffard A, Dropinski JF, Balkovec J (1997) In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob Agents Chemother 41(11):2326–2332

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berkow EL, Angulo D, Lockhart SR (2017) In vitro activity of a novel glucan synthase inhibitor, SCY-078, against clinical isolates of Candida auris. Antimicrob Agents Chemother 61(7)

    Google Scholar 

  • Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC (2012) Hidden killers: human fungal infections. Sci Trans Med 4(165):165rv113

    Google Scholar 

  • Cabib E (1991) Differential inhibition of chitin synthetases 1 and 2 from Saccharomyces cerevisiae by polyoxin D and nikkomycins. Antimicrob Agents Chemother 35(1):170–173

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cassone A, Mason RE, Kerridge D (1981) Lysis of growing yeast-form cells of Candida albicans by echinocandin: a cytological study. Sabouraudia 19(2):97–110

    CAS  PubMed  Google Scholar 

  • Chen SC, Slavin MA, Sorrell TC (2011) Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 71(1):11–41

    PubMed  Google Scholar 

  • Cheung YY, Hui M (2017) Effects of Echinocandins in combination with Nikkomycin Z against invasive Candida albicans bloodstream isolates and the fks mutants. Antimicrob Agents Chemother 61(11)

    Google Scholar 

  • Clemons CV, Stevens DA (1997) Efficacy of nikkomycin Z against experimental pulmonary blastomycosis. Antimicrob Agents Chemother 41(9):2026–2028

    Google Scholar 

  • Cowen LE, Steinbach WJ (2008) Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance. Eukaryot Cell 7(5):747–764

    CAS  PubMed  PubMed Central  Google Scholar 

  • Douglas CM (2001) Fungal beta(1,3)-d-glucan synthesis. Med Mycol 39(Suppl 1):55–66

    CAS  PubMed  Google Scholar 

  • Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M et al (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-d-glucan synthase. Proc Natl Acad Sci USA 91(26):12907–12911

    CAS  PubMed  Google Scholar 

  • Ene IV, Walker LA, Schiavone M, Lee KK, Martin-Yken H, Dague E, Gow NA, Munro CA, Brown AJ (2015) Cell wall remodeling enzymes modulate fungal cell wall elasticity and osmotic stress resistance. MBio 6(4):e00986

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eng WK, Faucette L, McLaughlin MM, Cafferkey R, Koltin Y, Morris RA, Young PR, Johnson RK, Livi GP (1994) The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth. Gene 151(1–2):61–71

    CAS  PubMed  Google Scholar 

  • Farmakiotis D, Tarrand JJ, Kontoyiannis DP (2014) Drug-resistant Candida glabrata infection in cancer patients. Emerg Infect Dis 20(11):1833–1840

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS (2009a) Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-d-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother 53(9):3690–3699

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Effron G, Park S, Perlin DS (2009b) Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints. Antimicrob Agents Chemother 53(1):112–122

    CAS  PubMed  Google Scholar 

  • Gaughran JP, Lai MH, Kirsch DR, Silverman SJ (1994) Nikkomycin Z is a specific inhibitor of Saccharomyces cerevisiae chitin synthase isozyme Chs3 in vitro and in vivo. J Bacteriol 176(18):5857–5860

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gebremariam T, Alkhazraji S, Alqarihi A, Jeon HH, Gu Y, KapoorM, Shaw KJ, Ibrahim AS (2019) APX001 Is effective in the treatment of murine invasive pulmonary aspergillosis.” Antimicrob Agents Chemother 63(2)

    Google Scholar 

  • Ghannoum M, Long L, Larkin EL, Isham N, Sherif R, Borroto-Esoda K, Barat S, Angulo D (2018) Evaluation of the antifungal activity of the novel oral glucan synthase inhibitor scy-078, singly and in combination, for the treatment of invasive Aspergillosis. Antimicrob Agents Chemother 62(6)

    Google Scholar 

  • Ghannoum M, Long L, HagerC, Borroto-Esoda K, Barat S, Angulo D (2019) Efficacy of Oral Ibrexafungerp (IBX, Formerly SCY-078) in the Treatment of Candida auris infection in a murine disseminated model. ASM Microbe2019. San Francisco

    Google Scholar 

  • Goldberg J, Connolly P, Schnizlein-Bick C, Durkin M, Kohler S, Smedema M, Brizendine E, Hector R, Wheat J (2000) Comparison of nikkomycin Z with amphotericin B and itraconazole for treatment of histoplasmosis in a murine model. Antimicrob Agents Chemother 44(6):1624–1629

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gow NAR, Latge JP, Munro CA (2017) The fungal cell wall: structure, biosynthesis, and function. Microbiol Spectr 5(3)

    Google Scholar 

  • Gunasekera A, Alvarez FJ, Douglas LM, Wang HX, Rosebrock AP, Konopka JB (2010) Identification of GIG1, a GlcNAc-induced gene in Candida albicans needed for normal sensitivity to the chitin synthase inhibitor nikkomycin Z. Eukaryot Cell 9(10):1476–1483

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hager CL, Larkin EL, Long L, Zohra Abidi F, Shaw KJ, Ghannoum MA (2018) In vitro and in vivo evaluation of the antifungal activity of APX001A/APX001 against Candida auris. Antimicrob Agents Chemother 62(3)

    Google Scholar 

  • Hall RA, Gow NA (2013) Mannosylation in Candida albicans: role in cell wall function and immune recognition. Mol Microbiol 90(6):1147–1161

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hata K, Horii T, Miyazaki M, Watanabe NA, Okubo M, Sonoda J, Nakamoto K, Tanaka K, Shirotori S, Murai N, Inoue S, Matsukura M, Abe S, Yoshimatsu K, Asada M (2011) Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis. Antimicrob Agents Chemother 55(10):4543–4551

    CAS  PubMed  PubMed Central  Google Scholar 

  • Healey KR, Perlin DS (2018) Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata. J Fungi (Basel) 4(3) (pii: E105)

    Google Scholar 

  • Healey KR, Katiyar SK, Raj S, Edlind TD (2012) CRS-MIS in Candida glabrata: sphingolipids modulate echinocandin-Fks interaction. Mol Microbiol 86(2):303–313

    CAS  PubMed  PubMed Central  Google Scholar 

  • Healey KR, Kordalewska M, Jimenez Ortigosa C, Singh A, Berrio I, Chowdhary A, Perlin DS (2018) Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility. Antimicrob Agents Chemother 62(10)

    Google Scholar 

  • Hohl TM, Feldmesser M, Perlin DS, Pamer EG (2008) Caspofungin modulates inflammatory responses to Aspergillus fumigatus through stage-specific effects on fungal beta-glucan exposure. J Infect Dis 198(2):176–185

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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(2):1248–1251

    PubMed  PubMed Central  Google Scholar 

  • Jimenez-Ortigosa C, Perez WB, Angulo D, Borroto-Esoda K, Perlin DS (2017) De novo acquisition of resistance to SCY-078 in Candida glabrata involves FKS mutations that both overlap and are distinct from those conferring echinocandin resistance. Antimicrob Agents Chemother 61(9)

    Google Scholar 

  • Kinoshita T (2016) Glycosylphosphatidylinositol (GPI) anchors: biochemistry and cell biology: introduction to a thematic review series. J Lipid Res 57(1):4–5

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kitamura A, Someya K, Hata M, Nakajima R, Takemura M (2009) Discovery of a small-molecule inhibitor of {beta}-1,6-glucan synthesis. Antimicrob Agents Chemother 53(2):670–677

    CAS  PubMed  Google Scholar 

  • Krishnan BR, James KD, Polowy K, Bryant BJ, Vaidya A, Smith S, Laudeman CP (2017) CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J Antibiot (Tokyo) 70(2):130–135

    CAS  Google Scholar 

  • Kucharikova S, Tournu H, Lagrou K, Van Dijck P, Bujdakova H (2011) Detailed comparison of Candida albicans and Candida glabrata biofilms under different conditions and their susceptibility to caspofungin and anidulafungin. J Med Microbiol 60(Pt 9):1261–1269

    CAS  PubMed  Google Scholar 

  • Kurtz MB, Douglas C, Marrinan J, Nollstadt K, Onishi J, Dreikorn S, Milligan J, Mandala S, Thompson J, Balkovec JM et al (1994a) Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob Agents Chemother 38(12):2750–2757

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kurtz MB, Heath IB, Marrinan J, Dreikorn S, Onishi J, Douglas C (1994b) Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-d-glucan synthase. Antimicrob Agents Chemother 38(7):1480–1489

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lamoth F, Alexander BD (2015) Antifungal activities of SCY-078 (MK-3118) and standard antifungal agents against clinical non-Aspergillus mold isolates. Antimicrob Agents Chemother 59(7):4308–4311

    CAS  PubMed  PubMed Central  Google Scholar 

  • Larkin EL, Long L, Isham N, Borroto-Esoda K, Barat S, Angulo D, Wring S, Ghannoum M (2019) A novel 1,3-beta-d-glucan inhibitor, Ibrexafungerp (Formerly SCY-078), shows potent activity in the lower pH environment of vulvovaginitis. Antimicrob Agents Chemother 63(5)

    Google Scholar 

  • Latge JP (2007) The cell wall: a carbohydrate armour for the fungal cell. Mol Microbiol 66(2):279–290

    CAS  PubMed  Google Scholar 

  • Latge JP (2010) Tasting the fungal cell wall. Cell Microbiol 12(7):863–872

    CAS  PubMed  Google Scholar 

  • Latge JP, Beauvais A, Chamilos G (2017) The cell wall of the human fungal pathogen Aspergillus fumigatus: biosynthesis, organization, immune response, and virulence. Annu Rev Microbiol 71:99–116

    CAS  PubMed  Google Scholar 

  • Lee KK, Kubo K, Abdelaziz JA, Cunningham I, de Silva Dantas A, Chen X, Okada H, Ohya Y, Gow NAR (2018) Yeast species-specific, differential inhibition of β-1,3-glucan synthesis by poacic acid and caspofungin. Cell Surf 2018(3):12–25

    Google Scholar 

  • Lenardon MD, Munro CA, Gow NA (2010) Chitin synthesis and fungal pathogenesis. Curr Opin Microbiol 13(4):416–423

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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(2):1265–1272

    PubMed  PubMed Central  Google Scholar 

  • Lepak AJ, Zhao M, VanScoy B, Ambrose PG, Andes DR (2018) Pharmacodynamics of a long-acting echinocandin, CD101, in a neutropenic invasive-candidiasis murine model using an extended-interval dosing design. Antimicrob Agents Chemother 62(2)

    Google Scholar 

  • Lesage G, Bussey H (2006) Cell wall assembly in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 70(2):317–343

    CAS  PubMed  PubMed Central  Google Scholar 

  • Levin DE (2011) Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics 189(4):1145–1175

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis JS 2nd, Wiederhold NP, Wickes BL, Patterson TF, Jorgensen JH (2013) Rapid emergence of echinocandin resistance in Candida glabrata resulting in clinical and microbiologic failure. Antimicrob Agents Chemother 57(9):4559–4561

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mann PA, McLellan CA, Koseoglu S, Si Q, Kuzmin E, Flattery A, Harris G, Sher X, Murgolo N, Wang H, Devito K, de Pedro N, Genilloud O, Kahn JN, Jiang B, Costanzo M, Boone C, Garlisi CG, Lindquist S, Roemer T (2015) Chemical genomics-based antifungal drug discovery: targeting Glycosylphosphatidylinositol (GPI) precursor biosynthesis. ACS Infect Dis 1(1):59–72

    CAS  PubMed  Google Scholar 

  • Mansbach R, Shaw KJ, Hodges MR, Coleman S, Fitzsimmons ME (2017) Absorption, distribution, and excretion of [14C]-APX001 after single-dose administration to rats and monkeys. IDWeek 2017. San Diego

    Google Scholar 

  • Matsukura M (2013) Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same. USA. US 8513287 B2

    Google Scholar 

  • Mazur P, Baginsky W (1996) In vitro activity of 1,3-beta-d-glucan synthase requires the GTP-binding protein Rho1. J Biol Chem 271(24):14604–14609

    CAS  PubMed  Google Scholar 

  • McCarthy PJ, Troke PF, Gull K (1985) Mechanism of action of nikkomycin and the peptide transport system of Candida albicans. J Gen Microbiol 131(4):775–780

    CAS  PubMed  Google Scholar 

  • Nett JE, Andes DR (2016) Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am 30(1):51–83

    PubMed  Google Scholar 

  • Niimi K, Maki K, Ikeda F, Holmes AR, Lamping E, Niimi M, Monk BC, Cannon RD (2006) Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrob Agents Chemother 50(4):1148–1155

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ong V, Hough G, Schlosser M, Bartizal K, Balkovec JM, James KD, Krishnan BR (2016) Preclinical evaluation of the stability, safety and efficacy of CD101, a novel echinocandin. Antimicrob Agents Chemother

    Google Scholar 

  • Onishi J, Meinz M, Thompson J, Curotto J, Dreikorn S, Rosenbach M, Douglas C, Abruzzo G, Flattery A, Kong L, Cabello A, Vicente F, Pelaez F, Diez MT, Martin I, Bills G, Giacobbe R, Dombrowski A, Schwartz R, Morris S, Harris G, Tsipouras A, Wilson K, Kurtz MB (2000) Discovery of novel antifungal (1,3)-beta-d-glucan synthase inhibitors. Antimicrob Agents Chemother 44(2):368–377

    CAS  PubMed  PubMed Central  Google Scholar 

  • Orlean PA (1982) (1,3)-beta-d-glucan synthase from budding and filamentous cultures of the dimorphic fungus Candida albicans. Eur J Biochem 127(2):397–403

    CAS  PubMed  Google Scholar 

  • Ostrosky-Zeichner L (2013) Candida glabrata and FKS mutations: witnessing the emergence of the true multidrug-resistant Candida. Clin Infect Dis 56(12):1733–1734

    PubMed  Google Scholar 

  • Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD (2016) Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America. Clin Infect Dis 62(4):e1–e50

    PubMed  Google Scholar 

  • Park S, Kelly R, Kahn JN, Robles J, Hsu MJ, Register E, Li W, Vyas V, Fan H, Abruzzo G, Flattery A, Gill C, Chrebet G, Parent SA, Kurtz M, Teppler H, Douglas CM, Perlin DS (2005) Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother 49(8):3264–3273

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pelaez F, Cabello A, Platas G, Diez MT, Gonzalez del Val A, Basilio A, Martan I, Vicente F, Bills GE, Giacobbe RA, Schwartz RE, Onish JC, Meinz MS, Abruzzo GK, Flattery AM, Kong L, Kurtz MB (2000) The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms. Syst Appl Microbiol 23(3):333–343

    CAS  PubMed  Google Scholar 

  • Perfect JR (2017) The antifungal pipeline: a reality check. Nat Rev Drug Discov 16(9):603–616

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perlin DS (2015) Echinocandin resistance in Candida. Clin Infect Dis 61(Suppl 6):S612–S617

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A (2017) The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis 17(12):e383–e392

    PubMed  Google Scholar 

  • Pfaller MA, Watanabe N, Castanheira M, Messer SA, Jones RN (2011) Pre-clinical development of antifungal susceptibility test methods for the testing of the novel antifungal agent E1210 versus Candida: comparison of CLSI and European committee on antimicrobial susceptibility testing methods. J Antimicrob Chemother 66(11):2581–2584

    CAS  PubMed  Google Scholar 

  • Pfaller MA, Messer SA, Rhomberg PR, Borroto-Esoda K, Castanheira M (2017a) Differential activity of the oral glucan synthase inhibitor SCY-078 against wild-type and echinocandin-resistant strains of candida species. Antimicrob Agents Chemother 61(8)

    Google Scholar 

  • Pfaller MA, Messer SA, Rhomberg PR, Castanheira M (2017b) Activity of a long-acting echinocandin (CD101) and seven comparator antifungal agents tested against a global collection of contemporary invasive fungal isolates in the SENTRY 2014 antifungal surveillance program. Antimicrob Agents Chemother 61(3) (pii: e02045-16)

    Google Scholar 

  • Pfaller MA, Huband MD, Flamm RK, Bien PA, Castanheira M (2019) In vitro activity of APX001A (Manogepix) and comparator agents against 1,706 fungal isolates collected during an international surveillance program (2017). Antimicrob Agents Chemother

    Google Scholar 

  • Pham CD, Iqbal N, Bolden CB, Kuykendall RJ, Harrison LH, Farley MM, Schaffner W, Beldavs ZG, Chiller TM, Park BJ, Cleveland AA, Lockhart SR (2014) Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance. Antimicrob Agents Chemother 58(8):4690–4696

    PubMed  PubMed Central  Google Scholar 

  • Pittet M, Conzelmann A (2007) Biosynthesis and function of GPI proteins in the yeast Saccharomyces cerevisiae. Biochim Biophys Acta 1771(3):405–420

    CAS  PubMed  Google Scholar 

  • Preechasuth K, Anderson JC, Peck SC, Brown AJ, Gow NA, Lenardon MD (2015) Cell wall protection by the Candida albicans class I chitin synthases. Fungal Genet Biol 82:264–276

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rispail N, Soanes DM, Ant C, Czajkowski R, Grunler A, Huguet R, Perez-Nadales E, Poli A, Sartorel E, Valiante V, Yang M, Beffa R, Brakhage AA, Gow NA, Kahmann R, Lebrun MH, Lenasi H, Perez-Martin J, Talbot NJ, Wendland J, Di Pietro A (2009) Comparative genomics of MAP kinase and calcium-calcineurin signalling components in plant and human pathogenic fungi. Fungal Genet Biol 46(4):287–298

    CAS  PubMed  Google Scholar 

  • Rosenwald AG, Arora G, Ferrandino R, Gerace EL, Mohammednetej M, Nosair W, Rattila S, Subic AZ, Rolfes R (2016) Identification of genes in Candida glabrata conferring altered responses to Caspofungin, a cell wall synthesis inhibitor. G3 (Bethesda) 6(9):2893–2907

    Google Scholar 

  • Ruiz-Herrera J, San-Blas G (2003) Chitin synthesis as target for antifungal drugs. Curr Drug Targets Infect Disord 3(1):77–91

    CAS  PubMed  Google Scholar 

  • Sagane K, Umemura M, Ogawa-Mitsuhashi K, Tsukahara K, Yoko-o T, Jigami Y (2011) Analysis of membrane topology and identification of essential residues for the yeast endoplasmic reticulum inositol acyltransferase Gwt1p. J Biol Chem 286(16):14649–14658

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sandison T, Ong V, Lee J, Thye D (2017) Safety and pharmacokinetics of CD101 IV, a novel echinocandin, in healthy adults. Antimicrob Agents Chemother 61(2)

    Google Scholar 

  • Sawistowska-Schroder ET, Kerridge D, Perry H (1984) Echinocandin inhibition of 1,3-beta-d-glucan synthase from Candida albicans. FEBS Lett 173(1):134–138

    CAS  PubMed  Google Scholar 

  • Schell WA, Jones AM, Borroto-Esoda K, Alexander BD (2017) Antifungal activity of SCY-078 and standard antifungal agents against 178 clinical isolates of resistant and susceptible Candida species. Antimicrob Agents Chemother 61(11)

    Google Scholar 

  • Schmatz DM, Powles M, McFadden DC, Pittarelli LA, Liberator PA, Anderson JW (1991) Treatment and prevention of Pneumocystis carinii pneumonia and further elucidation of the P. carinii life cycle with 1,3-b-glucan synthesis inhibitor L-671,329. J Protozool 38(6):151S–153S

    CAS  PubMed  Google Scholar 

  • Sekiya-Kawasaki M, Abe M, Saka A, Watanabe D, Kono K, Minemura-Asakawa M, Ishihara S, Watanabe T, Ohya Y (2002) Dissection of upstream regulatory components of the Rho1p effector, 1,3-beta-glucan synthase, in Saccharomyces cerevisiae. Genetics 162(2):663–676

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shields RK, Nguyen MH, Press EG, Kwa AL, Cheng S, Du C, Clancy CJ (2012) The presence of an FKS mutation rather than MIC is an independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due to Candida glabrata. Antimicrob Agents Chemother 56(9):4862–4869

    CAS  PubMed  PubMed Central  Google Scholar 

  • Slater JL, Howard SJ, Sharp A, Goodwin J, Gregson LM, Alastruey-Izquierdo A, Arendrup MC, Warn PA, Perlin DS, Hope WW (2011) Disseminated Candidiasis caused by Candida albicans with amino acid substitutions in Fks1 at position Ser645 cannot be successfully treated with micafungin. Antimicrob Agents Chemother 55(7):3075–3083

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taft CS, Selitrennikoff CP (1990) Cilofungin inhibition of (1-3)-beta-glucan synthase: the lipophilic side chain is essential for inhibition of enzyme activity. J Antibiot (Tokyo) 43(4):433–437

    CAS  Google Scholar 

  • Traxler P, Gruner J, Auden JA (1977) Papulacandins, a new family of antibiotics with antifungal activity, I. Fermentation, isolation, chemical and biological characterization of papulacandins A, B, C, D and E. J Antibiot (Tokyo) 30(4):289–296

    CAS  Google Scholar 

  • Valdivia RH, Schekman R (2003) The yeasts Rho1p and Pkc1p regulate the transport of chitin synthase III (Chs3p) from internal stores to the plasma membrane. Proc Natl Acad Sci USA 100(18):10287–10292

    Google Scholar 

  • Viriyakosol S, Kapoor M, Okamoto S, Covel J, Soltow QA, Trzoss M, Shaw KJ, Fierer J (2019) APX001 and other Gwt1 inhibitor prodrugs are effective in experimental Coccidioides immitis pneumonia. Antimicrob Agents Chemother 63(2)

    Google Scholar 

  • Wheeler RT, Fink GR (2006) A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog 2(4):e35

    PubMed  PubMed Central  Google Scholar 

  • Yadan JC, Gonneau M, Sarthou P, Le Goffic F (1984) Sensitivity to nikkomycin Z in Candida albicans: role of peptide permeases. J Bacteriol 160(3):884–888

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zambias RA, Hammond ML, Heck JV, Bartizal K, Trainor C, Abruzzo G, Schmatz DM, Nollstadt KM (1992) Preparation and structure-activity relationships of simplified analogues of the antifungal agent cilofungin: a total synthesis approach. J Med Chem 35(15):2843–2855

    CAS  PubMed  Google Scholar 

  • Zhang D, Miller MJ (1999) Polyoxins and nikkomycins: progress in synthetic and biological studies. Curr Pharm Des 5(2):73–99

    CAS  PubMed  Google Scholar 

  • Zhao Y, Perez WB, Jimenez-Ortigosa C, Hough G, Locke JB, Ong V, Bartizal K, Perlin DS (2016) CD101: a novel long-acting echinocandin. Cell Microbiol 18(9):1308–1316

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Prideaux B, Nagasaki Y, Lee MH, Chen PY, Blanc L, Ho H, Clancy CJ, Nguyen MH, Dartois V, Perlin DS (2017) Unraveling drug penetration of echinocandin antifungals at the site of infection in an intra-abdominal abscess model. Antimicrob Agents Chemother 61(10)

    Google Scholar 

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (AI109025) and Astellas (Reference Center for Molecular Evaluation of Drug) to D.S.P.

Disclosures

Dr. Perlin serves on scientific advisory boards and/or receives grant support from Merck, Astellas, Synexus, Cidara, and Amplyx.

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  1. Center for Discovery and Innovation, 340 Kingsland Street, Nutley, 07110, USA

    David S. Perlin

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  1. David S. Perlin
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Correspondence to David S. Perlin .

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  1. Foundation for Research and Technology-Hellas (FORTH), Institute of Molecular Biology and Technology, Heraklion, Crete, Greece

    Jean-Paul Latgé

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Perlin, D.S. (2019). Cell Wall-Modifying Antifungal Drugs. In: Latgé, JP. (eds) The Fungal Cell Wall . Current Topics in Microbiology and Immunology, vol 425. Springer, Cham. https://doi.org/10.1007/82_2019_188

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