In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four Candida auris Clades

• Published in: Pharmaceutics 2023-04, Vol.15 (5), p.1365
• Main Authors: Adnan, Awid, Borman, Andrew M, Tóth, Zoltán, Forgács, Lajos, Kovács, Renátó, Balázsi, Dávid, Balázs, Bence, Udvarhelyi, Gergely, Kardos, Gábor, Majoros, László
• Format: Article
• Language: English
• Subjects: Antifungal agents; chitin synthase inhibitor; echinocandins; Genomes; Mortality; Mutation; Ribosomal DNA; synergism; time–kill methodology
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics15051365

is a multidrug-resistant pathogen against which echinocandins are the drug of choice. However, information on how the chitin synthase inhibitor nikkomycin Z influences the killing activities of echinocandins against is currently lacking. We determined the killing activities of anidulafungin and micafungin (0.25, 1, 8, 16 and 32 mg/L each) with and without nikkomycin Z (8 mg/L) against 15 isolates representing four clades (South Asian n = 5; East Asian n = 3; South African n = 3; South American n = 4, two of which were of environmental origin). Two and one isolates from the South Asian clade harbored mutations in the hot-spot 1 (S639Y and S639P) and 2 (R1354H) regions of the gene, respectively. The anidulafungin, micafungin and nikkomycin Z MIC ranges were 0.015-4, 0.03-4 and 2->16 mg/L, respectively. Anidulafungin and micafungin alone exerted weak fungistatic activity against wild-type isolates and the isolate with a mutation in the hot-spot 2 region of but was ineffective against the isolates with a mutation in the hot-spot 1 region. The nikkomycin Z killing curves were always similar to their respective controls. Twenty-two of sixty (36.7%) anidulafungin plus nikkomycin Z and twenty-four of sixty (40%) micafungin plus nikkomycin Z combinations produced at least 100-fold decreases in the CFUs (synergy), with a 41.7% and 20% fungicidal effect, respectively, against wild-type isolates. Antagonism was never observed. Similar results were found with the isolate with a mutation in hot-spot 2 of , but the combinations were ineffective against the two isolates with prominent mutations in hot-spot 1 of . The simultaneous inhibition of β-1,3 glucan and chitin synthases in wild-type isolates produced significantly greater killing rates than either drug alone. Further studies are warranted to verify the clinical efficacy of echinocandin plus nikkomycin Z combinations against echinocandin susceptible isolates.