Perturbations of phosphatidate cytidylyltransferase (CdsA) mediate daptomycin resistance in Streptococcus mitis/oralis by a novel mechanism
| العنوان: | Perturbations of phosphatidate cytidylyltransferase (CdsA) mediate daptomycin resistance in Streptococcus mitis/oralis by a novel mechanism |
|---|---|
| المؤلفون: | Paul M. Sullam, Arnold S. Bayer, Cristina Garcia-de-la-Maria, Kym F. Faull, Michael J. Rybak, Nagendra N. Mishra, Truc T. Tran, Richard A. Proctor, José M. Miró, Cesar A. Arias, Ravin Seepersaud, Alexander J. Yoon |
| المصدر: | Repositorio U. El Bosque Universidad El Bosque instacron:Universidad El Bosque Antimicrobial agents and chemotherapy, vol 61, iss 4 |
| بيانات النشر: | American Society for Microbiology, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Neutrophils, Drug Resistance, Streptococcus mitis/orali, Cytidine Diphosphate, chemistry.chemical_compound, Cardiolipinas, Streptococcus mitis, Cardiolipin, Pharmacology (medical), education.field_of_study, biology, Bacterial, Lipopeptide, Pharmacology and Pharmaceutical Sciences, Phosphatidate cytidylyltransferase, Nucleotidyltransferases, Anti-Bacterial Agents, Infectious Diseases, 5.1 Pharmaceuticals, Medical Microbiology, Cloranfenicol, Daptomycin resistance, Development of treatments and therapeutic interventions, Infection, medicine.drug, 030106 microbiology, Antimicrobial peptides, Population, Microbial Sensitivity Tests, Gram-Positive Bacteria, Microbiology, 03 medical and health sciences, Daptomycin, Mechanisms of Resistance, Drug Resistance, Bacterial, medicine, education, Péptidos catiónicos antimicrobianos, Pharmacology, Streptococcus oralis, biology.organism_classification, 030104 developmental biology, chemistry, Streptococcus mitis/oralis, Antimicrobial Resistance |
| الوصف: | Streptococcus mitis/oralis is an important pathogen, causing life-threatening infections such as endocarditis and severe sepsis in immunocompromised patients. The β-lactam antibiotics are the usual therapy of choice for this organism, but their effectiveness is threatened by the frequent emergence of resistance. The lipopeptide daptomycin (DAP) has been suggested for therapy against such resistant S. mitis/oralis strains due to its in vitro bactericidal activity and demonstrated efficacy against other Gram-positive pathogens. Unlike other bacteria, however, S. mitis/oralis has the unique ability to rapidly develop stable, high-level resistance to DAP upon exposure to the drug both in vivo and in vitro . Using isogenic DAP-susceptible and DAP-resistant S. mitis/oralis strain pairs, we describe a mechanism of resistance to both DAP and cationic antimicrobial peptides that involves loss-of-function mutations in cdsA (encoding a phosphatidate cytidylyltransferase). CdsA catalyzes the synthesis of cytidine diphosphate-diacylglycerol, an essential phospholipid intermediate for the production of membrane phosphatidylglycerol and cardiolipin. DAP-resistant S. mitis/oralis strains demonstrated a total disappearance of phosphatidylglycerol, cardiolipin, and anionic phospholipid microdomains from membranes. In addition, these strains exhibited cross-resistance to cationic antimicrobial peptides from human neutrophils (i.e., hNP-1). Interestingly, CdsA-mediated changes in phospholipid metabolism were associated with DAP hyperaccumulation in a small subset of the bacterial population, without any binding by the remaining larger population. Our results indicate that CdsA is the major mediator of high-level DAP resistance in S. mitis/oralis and suggest a novel mechanism of bacterial survival against attack by antimicrobial peptides of both innate and exogenous origins. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::030c90618ed380450812f94d1e3d7da0Test https://europepmc.org/articles/PMC5365703Test/ |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....030c90618ed380450812f94d1e3d7da0 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |