The Burkholderia pseudomallei Enoyl-Acyl Carrier Protein Reductase FabI1 Is Essential for In Vivo Growth and Is the Target of a Novel Chemotherapeutic with Efficacy
| العنوان: | The Burkholderia pseudomallei Enoyl-Acyl Carrier Protein Reductase FabI1 Is Essential for In Vivo Growth and Is the Target of a Novel Chemotherapeutic with Efficacy |
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| المؤلفون: | Drew A. Rholl, Herbert P. Schweizer, Jason E. Cummings, Richard A. Slayden, Luke C. Kingry, Peter J. Tonge |
| المصدر: | Antimicrobial Agents and Chemotherapy. 58:931-935 |
| بيانات النشر: | American Society for Microbiology, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Burkholderia pseudomallei, Melioidosis, Enoyl-acyl carrier protein reductase, Mutant, Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific), Biology, Reductase, Isozyme, Microbiology, Gene Knockout Techniques, Mice, Bacterial Proteins, In vivo, medicine, Animals, Experimental Therapeutics, Pharmacology (medical), Enzyme Inhibitors, Pharmacology, chemistry.chemical_classification, medicine.disease, biology.organism_classification, Survival Analysis, Anti-Bacterial Agents, Isoenzymes, Treatment Outcome, Infectious Diseases, Enzyme, chemistry, Mutation, Female |
| الوصف: | The bacterial fatty acid biosynthesis pathway is a validated target for the development of novel chemotherapeutics. However, since Burkholderia pseudomallei carries genes that encode both FabI and FabV enoyl-acyl carrier protein (ACP) reductase homologues, the enoyl-ACP reductase that is essential for in vivo growth needs to be defined so that the correct drug target can be chosen for development. Accordingly, Δ fabI1 , Δ fabI2 , and Δ fabV knockout strains were constructed and tested in a mouse model of infection. Mice infected with a Δ fabI1 strain did not show signs of morbidity, mortality, or dissemination after 30 days of infection compared to the wild-type and Δ fabI2 and Δ fabV mutant strains that had times to mortality of 60 to 84 h. Although signs of morbidity and mortality of Δ fabI2 and Δ fabV strains were not significantly different from those of the wild-type strain, a slight delay was observed. A FabI1-specific inhibitor was used to confirm that inhibition of FabI1 results in reduced bacterial burden and efficacy in an acute B. pseudomallei murine model of infection. This work establishes that FabI1 is required for growth of Burkholderia pseudomallei in vivo and is a potential molecular target for drug development. |
| تدمد: | 1098-6596 0066-4804 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1e1d1effeb80f5e835f940d5504e331 https://doi.org/10.1128/aac.00176-13 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d1e1d1effeb80f5e835f940d5504e331 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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