Daptomycin resistance in Enterococcus faecium can be delayed by disruption of the LiaFSR stress response pathway
| العنوان: | Daptomycin resistance in Enterococcus faecium can be delayed by disruption of the LiaFSR stress response pathway |
|---|---|
| المؤلفون: | William R. Miller, Truc T. Tran, Adeline Supandy, Heer H. Mehta, Cesar A. Arias, Yousif Shamoo, Kathryn Beabout, Amy G. Prater |
| المساهمون: | Prater, Amy G. [0000-0001-6618-5130], Miller, William R. [0000-0002-1518-2973] |
| المصدر: | Repositorio U. El Bosque Universidad El Bosque instacron:Universidad El Bosque Antimicrob Agents Chemother |
| بيانات النشر: | Cold Spring Harbor Laboratory, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Resistencia antibiótica, Antibiotic resistance, Enterococcus faecium, Enterococo, Microbial Sensitivity Tests, Genome, Enterococcus faecalis, Microbiology, 03 medical and health sciences, Bacterial Proteins, Daptomycin, Mechanisms of Resistance, Drug Resistance, Bacterial, medicine, Humans, Drug resistance evolution, Pharmacology (medical), Allele, Gram-Positive Bacterial Infections, 030304 developmental biology, Pharmacology, Genetics, 0303 health sciences, Experimental evolution, biology, 030306 microbiology, Daptomycin resistance, Gene deletion, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Anti-Bacterial Agents, Response regulator, Infectious Diseases, Enterococcus, Daptomicina, Stress response pathway, Signal transduction, Adaptation, Evolución de la resistencia a los medicamentos, medicine.drug |
| الوصف: | The LiaFSR signaling pathway plays a major role in mediating daptomycin (DAP) resistance for both Enterococcus faecalis and Enterococcus faecium. LiaFSR inhibition induces DAP hypersusceptibility but could also potentially delay the acquisition of DAP resistance in a combinatorial therapy of DAP with a LiaFSR inhibitor. To evaluate the potential efficacy of this approach, the adaptation to DAP by both E. faecalis and E. faecium lacking a functional LiaFSR were examined. Here, clinical isolates of E. faecium with liaR deletions were evolved to DAP resistance using in vitro experimental evolution. Genomic analysis of resistant populations was used to identify both the alleles and their relative frequencies in driving DAP resistance. Microscopic and biochemical analyses were then employed to investigate how those adaptive alleles contributed to DAP resistance. We found that deletion of liaR from the E. faecium genome significantly delayed the onset of DAP resistance. Unsurprisingly, resistance strategies emerged eventually. These alternative strategies were influenced by both environment and ancestral genome. The delay in the acquisition of DAP resistance when liaR was deleted supports the concept of developing a LiaFSR pathway inhibitor to prolong DAP efficacy against enterococci. The loss of a functional LiaFSR pathway reset the adaptive landscape and forced adaptation to progress in new ways that were slower in providing DAP tolerance. The observed adaptive trajectories were strongly influenced by both the environment and ancestral genome. |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4c8674379ac63caeef573ff11fdb685f https://doi.org/10.1101/2020.06.23.168401 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4c8674379ac63caeef573ff11fdb685f |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |