In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> Clades
<i>Candida auris</i> 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 <i>C. auris</i> is currently lacking. W...
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| author | Awid Adnan Andrew M. Borman Zoltán Tóth Lajos Forgács Renátó Kovács Dávid Balázsi Bence Balázs Gergely Udvarhelyi Gábor Kardos László Majoros |
| author_facet | Awid Adnan Andrew M. Borman Zoltán Tóth Lajos Forgács Renátó Kovács Dávid Balázsi Bence Balázs Gergely Udvarhelyi Gábor Kardos László Majoros |
| author_sort | Awid Adnan |
| collection | DOAJ |
| description | <i>Candida auris</i> 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 <i>C. auris</i> 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 <i>C. auris</i> 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 <i>FKS1</i> 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 <i>FKS1</i> 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 <i>FKS1</i>, but the combinations were ineffective against the two isolates with prominent mutations in hot-spot 1 of <i>FKS1</i>. The simultaneous inhibition of β-1,3 glucan and chitin synthases in wild-type <i>C. auris</i> 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 <i>C. auris</i> isolates. |
| first_indexed | 2024-03-11T03:24:36Z |
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| issn | 1999-4923 |
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| last_indexed | 2024-03-11T03:24:36Z |
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| spelling | doaj.art-9f4049b00f6144a6ae5201a8b1483d872023-11-18T02:50:33ZengMDPI AGPharmaceutics1999-49232023-04-01155136510.3390/pharmaceutics15051365In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> CladesAwid Adnan0Andrew M. Borman1Zoltán Tóth2Lajos Forgács3Renátó Kovács4Dávid Balázsi5Bence Balázs6Gergely Udvarhelyi7Gábor Kardos8László Majoros9Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryUK National Mycology Reference Laboratory, UK Health Security Agency, Science Quarter, Southmead Hospital, Bristol BS10 5NB, UKDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Metagenomics, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary<i>Candida auris</i> 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 <i>C. auris</i> 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 <i>C. auris</i> 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 <i>FKS1</i> 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 <i>FKS1</i> 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 <i>FKS1</i>, but the combinations were ineffective against the two isolates with prominent mutations in hot-spot 1 of <i>FKS1</i>. The simultaneous inhibition of β-1,3 glucan and chitin synthases in wild-type <i>C. auris</i> 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 <i>C. auris</i> isolates.https://www.mdpi.com/1999-4923/15/5/1365time–kill methodologysynergismechinocandinschitin synthase inhibitor |
| spellingShingle | Awid Adnan Andrew M. Borman Zoltán Tóth Lajos Forgács Renátó Kovács Dávid Balázsi Bence Balázs Gergely Udvarhelyi Gábor Kardos László Majoros In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> Clades Pharmaceutics time–kill methodology synergism echinocandins chitin synthase inhibitor |
| title | In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> Clades |
| title_full | In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> Clades |
| title_fullStr | In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> Clades |
| title_full_unstemmed | In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> Clades |
| title_short | In Vitro Killing Activities of Anidulafungin and Micafungin with and without Nikkomycin Z against Four <i>Candida auris</i> Clades |
| title_sort | in vitro killing activities of anidulafungin and micafungin with and without nikkomycin z against four i candida auris i clades |
| topic | time–kill methodology synergism echinocandins chitin synthase inhibitor |
| url | https://www.mdpi.com/1999-4923/15/5/1365 |
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