Emergence of Daptomycin Resistance in Daptomycin-Naïve Rabbits with Methicillin-Resistant Staphylococcus aureus Prosthetic Joint Infection Is Associated with Resistance to Host Defense Cationic Peptides and mprF Polymorphisms

Mishra, Nagendra N.; Yang, Soo Jin; Chen, Liang; Muller, Claudette; Saleh‐Mghir, Azzam; Kuhn, Sebastian; Peschel, Andreas; Yeaman, Michael R.; Nast, Cynthia C.; Kreiswirth, Barry N.; Crémieux, A; Bayer, Arnold S.

doi:10.1371/journal.pone.0071151

Cited by 77 publications

(67 citation statements)

References 51 publications

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“…However, SNPs in mprF were the most frequently encountered, and were accompanied by an increase in resistance to daptomycin and other CAMPs (nisin and human CAMPs e.g., [75,79]). Most mprF gain-of-function SNPs are located in the flippase domain, and they generally increase the total amount of Lys-PG in the membrane as well as the amount of Lys-PG translocated to the outer surface of the cytoplasmic membrane (e.g., [77,78]). Interestingly, SNPs in the lysX gene in M. tuberculosis were recently discovered; this finding further supports the hypothesis that this system plays a role in virulence.…”

Section: Single Nucleotide Polymorphisms: Gain Of Function Mutations mentioning

confidence: 99%

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

Fields

Roy

2017

RNA Biology

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ABSTRACTtRNA-dependent addition of amino acids to lipids on the outer surface of the bacterial membrane results in decreased effectiveness of antimicrobials such as cationic antimicrobial peptides (CAMPs) that target the membrane, and increased virulence of several pathogenic species. After a brief introduction to CAMPs and the various bacterial resistance mechanisms used to counteract these compounds, this review focuses on recent advances in tRNA-dependent pathways for lipid modification in bacteria. Phenotypes associated with amino acid lipid modifications and regulation of their expression will also be discussed.

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Section: Single Nucleotide Polymorphisms: Gain Of Function Mutations mentioning

confidence: 99%

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

Fields

Roy

2017

RNA Biology

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“…Esta es una enzima bifuncional que se encarga de la adición de lisina (aminoácido de carga positiva) a residuos de fosfatidilglicerol en la capa interna de la membrana celular, formando lisilfosfatidilglicerol (L-FG), y de la translocación de L-FG desde la capa interna hacia la capa externa de la membrana (actividad de flipasa) (93)(94)(95). En cepas de S. aureus resistentes a la daptomicina se han descrito diversas mutaciones en el mprF (94) que parecen incrementar la actividad de esta enzima, contribuyendo al incremento de la carga positiva de la superficie celular (94)(95)(96). El operón dltABC, responsable de la adición de D-alanina a los ácidos teicoicos (lo que aumenta la carga positiva de la membrana), también se ha relacionado con la reducción de la sensibilidad a la daptomicina (97) y, por último, las mutaciones puntuales en los genes rpoB y rpoC (que codifican para las subunidades ß y ß' de la ARN polimerasa, respectivamente), se han asociado, igualmente, con la aparición de la resistencia a la daptomicina en S. aureus (92,98).…”

Section: Resistencia a La Daptomicina En Staphylococcus Aureusunclassified

Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina

et al. 2014

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Resistencia a antibióticos de última línea Contribución de los autores:Sandra Rincón: redacción de las siguientes secciones: resumen, introducción, problemas del uso de la vancomicina en infecciones causadas por Staphylococcus aureus, la vancomicina es obsoleta en el tratamiento de infecciones por enterococos multirresistentes, resistencia a cefalosporinas de última generación y conclusiones. Diana Panesso: redacción de la sección de resistencia a daptomicina. Lorena Díaz: redacción de la sección de resistencia a las oxazolidinonas y elaboración del cuadro 1. Lina P. Carvajal y Jinnethe Reyes: redacción de la sección de resistencia a tigeciclinas. Jinnethe Reyes: elaboración de la figura 1. José M. Munita: preparación, revisión y edición del manuscrito final. Lorena Díaz y José M. Munita: preparación y revisión de la versión final del manuscrito. Cesar A. Arias: diseño del esquema del artículo, revisión y corrección de la totalidad del manuscrito. REVISIÓN DE TEMA Biomédica 2014;34(Supl. En los últimos años se han desarrollado nuevas alternativas para el tratamiento de infecciones por patógenos Gram positivos multirresistentes, entre los cuales Staphylococcus aureus resistente a la meticilina (SARM) y los enterococos resistentes a la vancomicina (ERV) se consideran un verdadero reto terapéutico, y aunque el uso de la vancomicina en infecciones graves causadas por SARM ha generado serias dudas en los últimos años, continúa siendo escasa la información clínica de respaldo al uso de agentes terapéuticos que la superen en eficacia. El linezolid, la daptomicina y la tigeciclina son agentes que tienen actividad contra los cocos Gram positivos y que fueron aprobados e introducidos en la terapia clínica en la década pasada. Además, se han probado o están en las fases finales de desarrollo otros agentes como las cefalosporinas de última generación (ceftarolina y ceftobiprol). El propósito de esta revisión fue describir las nuevas alternativas terapéuticas, particularmente en la era posterior a la vancomicina, y repasar las características químicas más relevantes de los compuestos y su espectro de actividad, haciendo énfasis en sus mecanismos de acción y resistencia. This review focuses on discussing these newer antibiotics used in the "post-vancomycin" era with emphasis on relevant chemical characteristics, spectrum of antimicrobial activity, mechanisms of action and resistance, as well as their clinical utility.

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“…A hot spot for genetic changes that decrease susceptibility to daptomycin is the mprF (multipeptide resistance factor) gene (4,6). MprF is a bifunctional membrane protein responsible for adding lysine to phosphatidylglycerol (PG) and for flipping the positively charged lysyl-PG product to the outer leaflet of the cytoplasmic membrane (7).…”

mentioning

confidence: 99%

Stepwise Decrease in Daptomycin Susceptibility in Clinical Staphylococcus aureus Isolates Associated with an Initial Mutation in rpoB and a Compensatory Inactivation of the clpX Gene

Bæk

Thøgersen

Mogenssen

et al. 2015

Antimicrob Agents Chemother

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dDaptomycin is a lipopeptide antibiotic used clinically for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. The emergence of daptomycin-nonsusceptible S. aureus isolates during therapy is often associated with multiple genetic changes; however, the relative contributions of these changes to resistance and other phenotypic changes usually remain unclear. The present study was undertaken to investigate this issue using a genetically characterized series of four isogenic clinical MRSA strains derived from a patient with bacteremia before and during daptomycin treatment. The first strain obtained after daptomycin therapy carried a single-nucleotide polymorphism (SNP) in rpoB (RpoB A 477 D) that decreased susceptibility not only to daptomycin but also to vancomycin, ␤-lactams, and rifampin. Furthermore, the rpoB mutant exhibited pleiotropic phenotypes, including increased cell wall thickness, reduced expression of virulence traits, induced expression of the stress-associated transcriptional regulator Spx, and slow growth. A subsequently acquired loss-of-function mutation in clpX partly alleviated the growth defect conferred by the rpoB mutation without changing antibiotic susceptibility. The final isolate acquired three additional mutations, including an SNP in mprF (MprF S 295 L) known to confer daptomycin nonsusceptibility, and accordingly, this isolate was the only daptomycin-nonsusceptible strain of this series. Interestingly, in this isolate, the cell wall had regained the same thickness as that of the parental strain, while the level of transcription of the vraSR (cell wall stress regulator) was increased. In conclusion, this study illustrates how serial genetic changes selected in vivo contribute to daptomycin nonsusceptibility, growth fitness, and virulence traits. Staphylococcus aureus is a commensal bacterium that can cause a variety of both localized and more invasive infections. Due to its profound ability to acquire resistance to clinically relevant antibiotics, S. aureus remains a major clinical challenge worldwide (1). The most challenging antimicrobial resistance issue in S. aureus has been the evolution and dissemination of methicillinresistant S. aureus (MRSA) strains first in hospitals and later in the general community (1). MRSA infections are typically treated with last-line antibiotics, such as vancomycin and, more recently, daptomycin (DAP), a cyclic lipopeptide derived from Streptomyces roseosporus with bactericidal activity against a broad range of Gram-positive bacteria (2, 3). The mechanism of action of daptomycin has not been fully elucidated, but it is generally accepted that daptomycin inserts into the cytoplasmic membrane of Grampositive bacteria via a calcium-dependent pathway, leading to potassium efflux, membrane depolarization, and, eventually, cell death (2).The development of daptomycin nonsusceptibility (DAP-NS) in S. aureus seems to be a relatively rare phenomenon not involving horizontal gene transfer but, instead, taking place by a stepwise acqu...

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Emergence of Daptomycin Resistance in Daptomycin-Naïve Rabbits with Methicillin-Resistant Staphylococcus aureus Prosthetic Joint Infection Is Associated with Resistance to Host Defense Cationic Peptides and mprF Polymorphisms

Cited by 77 publications

References 51 publications

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina

Stepwise Decrease in Daptomycin Susceptibility in Clinical Staphylococcus aureus Isolates Associated with an Initial Mutation in rpoB and a Compensatory Inactivation of the clpX Gene

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