المؤلفون: Parsons, Joshua B., Sidders, Ashelyn E., Velez, Amanda Z., Hanson, Blake M., Angeles-Solano, Michelle, Ruffin, Felicia, Rowe, Sarah E., Arias, Cesar A., Fowler Jr., Vance G., Thaden, Joshua T., Conlon, Brian P.

المصدر: Proceedings of the National Academy of Sciences of the United States of America; 1/16/2024, Vol. 121 Issue 3, p1-9, 23p

مصطلحات موضوعية: GRAM-negative bacterial diseases, ESCHERICHIA coli, COUPLES therapy, ANTIBIOTICS, HYPNOTISM

مستخلص: Gram-negative bacterial bloodstream infections (GNB-BSI) are common and frequently lethal. Despite appropriate antibiotic treatment, relapse of GNB-BSI with the same bacterial strain is common and associated with poor clinical outcomes and high healthcare costs. The role of persister cells, which are sub-populations of bacteria that survive for prolonged periods in the presence of bactericidal antibiotics, in relapse of GNB-BSI is unclear. Using a cohort of patients with relapsed GNB-BSI, we aimed to determine how the pathogen evolves within the patient between the initial and subsequent episodes of GNB-BSI and how these changes impact persistence. Using Escherichia coli clinical bloodstream isolate pairs (initial and relapse isolates) from patients with relapsed GNB-BSI, we found that 4/11 (36%) of the relapse isolates displayed a significant increase in persisters cells relative to the initial bloodstream infection isolate. In the relapsed E. coli strain with the greatest increase in persisters (100-fold relative to initial isolate), we determined that the increase was due to a loss-of- function mutation in the ptsI gene encoding Enzyme I of the phosphoenolpyruvate phosphotransferase system. The ptsI mutant was equally virulent in a murine bacteremia infection model but exhibited 10-fold increased survival to antibiotic treatment. This work addresses the controversy regarding the clinical relevance of persister formation by providing compelling data that not only do high-persister mutations arise during bloodstream infection in humans but also that these mutants display increased survival to antibiotic challenge in vivo. [ABSTRACT FROM AUTHOR]

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المؤلفون: Khan, Ayesha, Davlieva, Milya, Panesso, Diana, Rincon, Sandra, Millera, William R., Diaz, Lorena, Reyes, Jinnethe, Cruz, Melissa R., Pemberton, Orville, Nguyen, April H., Siegel, Sara D., Planet, Paul J., Narechania, Apurva, Latorre, Mauricio, Rios, Rafael, Singh, Kavindra V., Ton-That, Hung, Garsin, Danielle A., Tran, Truc T., Shamoo, Yousif, Arias, Cesar A

مصطلحات موضوعية: Enterococos resistentes a la vancomicina, Farmacorresistencia microbiana, Estructuras de la membrana celular, Antibiotic resistance, Enterococcus faecalis, Daptomycin, Cell membrane adaptation, Antimicrobial, Peptides

الوصف: Bacteria have developed several evolutionary strategies to protect their cell membranes (CMs) from the attack of antibiotics and antimicrobial peptides (AMPs) produced by the innate immune system, including remodeling of phospholipid content and localization. Multidrug-resistant Enterococcus faecalis, an opportunistic human pathogen, evolves resistance to the lipopeptide daptomycin and AMPs by diverting the antibiotic away from critical septal targets using CM anionic phospholipid redistribution. The LiaFSR stress response system regulates this CM remodeling via the LiaR response regulator by a previously unknown mechanism. Here, we characterize a LiaR-regulated protein, LiaX, that senses daptomycin or AMPs and triggers protective CM remodeling. LiaX is surface exposed, and in daptomycin-resistant clinical strains, both LiaX and the N-terminal domain alone are released into the extracellular milieu. The N-terminal domain of LiaX binds daptomycin and AMPs (such as human LL-37) and functions as an extracellular sentinel that activates the cell envelope stress response. The C-terminal domain of LiaX plays a role in inhibiting the LiaFSR system, and when this domain is absent, it leads to activation of anionic phospholipid redistribution. Strains that exhibit LiaX-mediated CM remodeling and AMP resistance show enhanced virulence in the Caenorhabditis elegans model, an effect that is abolished in animals lacking an innate immune pathway crucial for producing AMPs. In conclusion, we report a mechanism of antibiotic and AMP resistance that couples bacterial stress sensing to major changes in CM architecture, ultimately also affecting host–pathogen interactions.

وصف الملف: application/pdf

العلاقة: Proceedings of the National Academy of Sciences, 1091-6490, Vol 116, Núm 52, pag 26925–26932; https://www.pnas.org/content/116/52/26925Test; http://hdl.handle.net/20.500.12495/2161Test; https://doi.org/10.1073/pnas.1916037116Test; instname:Universidad El Bosque; reponame: Repositorio Institucional Universidad El Bosque; repourl:https://repositorio.unbosque.edu.coTest

الإتاحة: https://doi.org/20.500.12495/2161Test
https://doi.org/10.1073/pnas.1916037116Test
https://hdl.handle.net/20.500.12495/2161Test