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In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales
OBJECTIVES: To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing Enterobacterales (CPE) clinical isolates and 6 in vitro selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants. METHODS: MICs of i...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581557/ https://www.ncbi.nlm.nih.gov/pubmed/34778107 http://dx.doi.org/10.3389/fcimb.2021.755763 |
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author | Wang, Wen Huang, Shifeng Zou, Chunhong Ding, Yanhui Wang, Huijuan Pu, Shuli Liao, Yunfeng Du, Hong Wang, Deqiang Chen, Liang Niu, Siqiang |
author_facet | Wang, Wen Huang, Shifeng Zou, Chunhong Ding, Yanhui Wang, Huijuan Pu, Shuli Liao, Yunfeng Du, Hong Wang, Deqiang Chen, Liang Niu, Siqiang |
author_sort | Wang, Wen |
collection | PubMed |
description | OBJECTIVES: To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing Enterobacterales (CPE) clinical isolates and 6 in vitro selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants. METHODS: MICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined via the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing. RESULTS: AUR alone showed little antibacterial activity with AUR MICs were greater than 64 μg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 μg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC(50) (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC(90) (1 to 0.25 μg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC(50) and MIC(90) reduced by 2-folding dilutions (0.25 to 0.0625 μg/mL) and 3-folding dilutions (2 to 0.25 μg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC(50) (0.0625 μg/mL) and MIC(90) (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 in vitro selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32->256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL). CONCLUSIONS: Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates in vitro. Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing Enterobacterales. |
format | Online Article Text |
id | pubmed-8581557 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85815572021-11-12 In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales Wang, Wen Huang, Shifeng Zou, Chunhong Ding, Yanhui Wang, Huijuan Pu, Shuli Liao, Yunfeng Du, Hong Wang, Deqiang Chen, Liang Niu, Siqiang Front Cell Infect Microbiol Cellular and Infection Microbiology OBJECTIVES: To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing Enterobacterales (CPE) clinical isolates and 6 in vitro selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants. METHODS: MICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined via the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing. RESULTS: AUR alone showed little antibacterial activity with AUR MICs were greater than 64 μg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 μg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC(50) (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC(90) (1 to 0.25 μg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC(50) and MIC(90) reduced by 2-folding dilutions (0.25 to 0.0625 μg/mL) and 3-folding dilutions (2 to 0.25 μg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC(50) (0.0625 μg/mL) and MIC(90) (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 in vitro selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32->256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL). CONCLUSIONS: Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates in vitro. Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing Enterobacterales. Frontiers Media S.A. 2021-10-28 /pmc/articles/PMC8581557/ /pubmed/34778107 http://dx.doi.org/10.3389/fcimb.2021.755763 Text en Copyright © 2021 Wang, Huang, Zou, Ding, Wang, Pu, Liao, Du, Wang, Chen and Niu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular and Infection Microbiology Wang, Wen Huang, Shifeng Zou, Chunhong Ding, Yanhui Wang, Huijuan Pu, Shuli Liao, Yunfeng Du, Hong Wang, Deqiang Chen, Liang Niu, Siqiang In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales |
title |
In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales
|
title_full |
In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales
|
title_fullStr |
In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales
|
title_full_unstemmed |
In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales
|
title_short |
In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales
|
title_sort | in vitro activity of auranofin in combination with aztreonam-avibactam against metallo-β-lactamase (mbl)-producing enterobacterales |
topic | Cellular and Infection Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581557/ https://www.ncbi.nlm.nih.gov/pubmed/34778107 http://dx.doi.org/10.3389/fcimb.2021.755763 |
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