Repurposing harmaline as a novel approach to reverse tmexCD1-toprJ1-mediated tigecycline resistance against klebsiella pneumoniae infections.
Microb Cell Fact
; 23(1): 152, 2024 May 24.
Article
em En
| MEDLINE
| ID: mdl-38790017
ABSTRACT
BACKGROUND:
A novel plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the "last-resort" antibiotic tigecycline.RESULTS:
In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance.CONCLUSION:
These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Infecções por Klebsiella
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Reposicionamento de Medicamentos
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Tigeciclina
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Harmalina
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Klebsiella pneumoniae
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Antibacterianos
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article