Perturbations of phosphatidate cytidylyltransferase (CdsA) mediate daptomycin resistance in Streptococcus mitis/oralis by a novel mechanism

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dc.contributor.authorMishra, Nagendra Nath
dc.contributor.authorTran, Truc T.
dc.contributor.authorSeepersaud, Ravin
dc.contributor.authorGarcía-De-La-Mària, Cristina
dc.contributor.authorFaull, Kym F.
dc.contributor.authorYoon, Alexander J.
dc.contributor.authorProctor, Richard A.
dc.contributor.authorMiró, José María
dc.contributor.authorRybak, Michael Joseph
dc.contributor.authorBayer, Arnold S.
dc.contributor.authorArias, César A.
dc.contributor.authorSullam, Paul M.
dc.date.accessioned2020-07-09T19:27:04Z
dc.date.available2020-07-09T19:27:04Z
dc.date.issued2017
dc.description.abstractenglishStreptococcus 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.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1128/aac.02435-16
dc.identifier.instnameinstname:Universidad El Bosquespa
dc.identifier.issn1098-6596
dc.identifier.reponamereponame:Repositorio Institucional Universidad El Bosquespa
dc.identifier.repourlhttps://repositorio.unbosque.edu.co
dc.identifier.urihttps://hdl.handle.net/20.500.12495/3389
dc.language.isoeng
dc.publisherAmerican Society for Microbiologyspa
dc.publisher.journalAntimicrobial agents and chemotherapyspa
dc.relation.ispartofseriesAntimicrobial agents and chemotherapy, 1098-6596, Vol. 61, Nro. 4, 2017spa
dc.relation.urihttps://aac.asm.org/content/61/4/e02435-16
dc.rights.accessrightshttps://purl.org/coar/access_right/c_abf2
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.accessrightsAcceso abierto
dc.rights.creativecommons2017-04
dc.rights.localAcceso abiertospa
dc.subject.decsPéptidos catiónicos antimicrobianosspa
dc.subject.decsCardiolipinasspa
dc.subject.decsCloranfenicolspa
dc.subject.keywordsStreptococcus mitis/oralispa
dc.subject.keywordsPhosphatidate cytidylyltransferasespa
dc.subject.keywordsDaptomycin resistancespa
dc.titlePerturbations of phosphatidate cytidylyltransferase (CdsA) mediate daptomycin resistance in Streptococcus mitis/oralis by a novel mechanismspa
dc.title.translatedPerturbations of phosphatidate cytidylyltransferase (CdsA) mediate daptomycin resistance in Streptococcus mitis/oralis by a novel mechanismspa
dc.type.coarhttps://purl.org/coar/resource_type/c_6501
dc.type.driverinfo:eu-repo/semantics/article
dc.type.hasversioninfo:eu-repo/semantics/publishedVersion
dc.type.localArtículo de revista

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