Phosphoethanolamine Modification of Lipid A in Colistin-Resistant Variants of Acinetobacter baumannii Mediated by the pmrAB Two-Component Regulatory System

Beceiro, Alejandro; Llobet, Enrique; Aranda, Jesús; Bengoechea, José A.; Doumith, Michel; Hornsey, Michael; Dhanji, Hiran; Chart, Henrik; Bou, Germán; Livermore, David M.; Woodford, Neil

doi:10.1128/aac.00079-11

Cited by 340 publications

(316 citation statements)

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“…In A. baumannii, the PmrAB system is implicated in colistin resistance, and requires at least two distinct genetic events: (i) at least one amino acid change in PmrB and (ii) upregulated expression of pmrA and pmrB, although the precise genetic events that cause pmrAB upregulation have not been defined (Beceiro et al, 2011). A limitation of the present study is that pmrAB upregulation was not examined.…”

Section: Resultsmentioning

confidence: 82%

“…Colistin resistance is associated with specific modification of the lipid A component of the outer membrane and is mediated by mutations in specific regions of the two-component regulation systems pmrA/B and phoP/Q (Beceiro et al, 2011). Tigecycline resistance has been associated with overexpression of a variety of efflux pumps (Deng et al, 2014;Hou et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Molecular identification of tigecycline- and colistin-resistant carbapenemase-producing Acinetobacter baumannii from a Greek hospital from 2011 to 2013

Mavroidi¹,

Likousi²,

Palla³

et al. 2015

Journal of Medical Microbiology

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An alarming increase in the resistance rates of tigecycline and colistin among carbapenemaseproducing Acinetobacter baumannii recovered from a Greek hospital over a 3-year period (2011-2013) was investigated. The antimicrobial resistance profiles and carbapenemase gene content were determined for a collection of colistin-and/or tigecycline-resistant carbapenemase-producing A. baumannii isolates (n542), which were recovered consecutively during the study period. A gradual increase in the incidence of bla OXA-23 producers was observed from 2011 to 2013. A cluster of 21 isolates comprised tigecycline-resistant bla OXA-23 producers displayed a single antimicrobial resistance pattern. The emergence of two bla OXA-23 producers resistant to both tigecycline and colistin was documented. Furthermore, determination of the mechanisms of colistin and tigecycline resistance and molecular typing by the tri-locus sequence typing (3LST) scheme for nine isolates recovered from bloodstream infections were performed. Out of nine isolates, five tigecycline-and two colistin-resistant isolates were bla OXA-23 producers of 3LST ST101 corresponding to the international clone II recovered during 2012-2013. All nine isolates were positive for the presence of the adeB gene of the AdeABC efflux pump. Three colistin-resistant isolates possessed novel substitutions in PmrB, which may be implicated in colistin resistance. To the best of our knowledge, this is the first report of the acquisition of tigecycline and colistin resistance among bla OXA-23 -producing A. baumannii of 3LST ST101 in Greece; thus, continuous surveillance and molecular characterization, prudent use of antibiotics and implementation of infection control measures for A. baumannii are urgent.

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Section: Resultsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Molecular identification of tigecycline- and colistin-resistant carbapenemase-producing Acinetobacter baumannii from a Greek hospital from 2011 to 2013

Mavroidi¹,

Likousi²,

Palla³

et al. 2015

Journal of Medical Microbiology

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“…Previous studies of colistin resistance in A. baumannii have found resistance to be mediated either by the complete loss of lipopolysaccharide (LPS) (Moffatt et al 2010), or by mutations at the pmr locus (Adams et al 2009;Beceiro et al 2011;Park et al 2011;Rolain et al 2012). The pmr locus is an auto-regulated two-component signal transduction system, which in addition to a sensor-kinase and response-regulator, also includes an ethanolamine transferase.…”

mentioning

confidence: 99%

Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment

et al. 2013

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Bacterial whole-genome sequencing (WGS) of human pathogens has provided unprecedented insights into the evolution of antibiotic resistance. Most studies have focused on identification of resistance mutations, leaving one to speculate on the fate of these mutants once the antibiotic selective pressure is removed. We performed WGS on longitudinal isolates of Acinetobacter baumannii from patients undergoing colistin treatment, and upon subsequent drug withdrawal. In each of the four patients, colistin resistance evolved via mutations at the pmr locus. Upon colistin withdrawal, an ancestral susceptible strain outcompeted resistant isolates in three of the four cases. In the final case, resistance was also lost, but by a compensatory inactivating mutation in the transcriptional regulator of the pmr locus. Notably, this inactivating mutation reduced the probability of reacquiring colistin resistance when subsequently challenged in vitro. On face value, these results supported an in vivo fitness cost preventing the evolution of stable colistin resistance. However, more careful analysis of WGS data identified genomic evidence for stable colistin resistance undetected by clinical microbiological assays. Transcriptional studies validated this genomic hypothesis, showing increased pmr expression of the initial isolate. Moreover, altering the environmental growth conditions of the clinical assay recapitulated the classification as colistin resistant. Additional targeted sequencing revealed that this isolate evolved undetected in a patient undergoing colistin treatment, and was then transmitted to other hospitalized patients, further demonstrating its stability in the absence of colistin. This study provides a unique window into mutational pathways taken in response to antibiotic pressure in vivo, and demonstrates the potential for genome sequence data to predict resistance phenotypes.

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“…La adición covalente de estas moléculas, que son de carga positiva, hacen que la carga neta del lípido A sea menos negativa, lo que altera el primer mecanismo de unión de la polimixina con su sitio blanco, que es la atracción electrostática 51 . Todo lo anterior se traduce en disminución de la afinidad del antimicrobiano por su sitio blanco 52 . Otro mecanismo asociado al aumento de resistencia a polimixinas es la adición de cadenas adicionales de ácidos grasos a la estructura del lípido A, lo que haría a la membrana externa menos penetrable para las polimixinas 53 .…”

Section: Mecanismos De Resistenciaunclassified

Colistín en la era post-antibiótica

Aguayo¹,

Mella²,

Riedel³

et al. 2016

Rev. chil. infectol.

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Phosphoethanolamine Modification of Lipid A in Colistin-Resistant Variants of Acinetobacter baumannii Mediated by the pmrAB Two-Component Regulatory System

Cited by 340 publications

References 50 publications

Molecular identification of tigecycline- and colistin-resistant carbapenemase-producing Acinetobacter baumannii from a Greek hospital from 2011 to 2013

Molecular identification of tigecycline- and colistin-resistant carbapenemase-producing Acinetobacter baumannii from a Greek hospital from 2011 to 2013

Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment

Colistín en la era post-antibiótica

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