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1. (Article ID: 3985)
Arroyo LA, Herrera CM, Fernandez L, Hankins JV, Trent MS, Hancock RE
The pmrCAB operon mediates polymyxin resistance in Acinetobacter baumannii ATCC 17978 and clinical isolates through phosphoethanolamine modification of lipid A
Antimicrobial Agents and Chemotherapy 55(8) (2011)
3743-3751
The emergence of multidrug resistance among Acinetobacter baumannii is leading to an increasing dependence on the use of polymyxins as last-hope antibiotics. Here, we utilized genetic and biochemical methods to define the involvement of the pmrCAB operon in polymyxin resistance in this organism. Sequence analysis of 16 polymyxin B-resistant strains, including 6 spontaneous mutants derived from strain ATCC 17978 and 10 clinical isolates from diverse sources, revealed that they had independent mutations in the pmrB gene, encoding a sensor kinase, or in the response regulator PmrA. Knockout of the pmrB gene in two mutants and two clinical isolates led to a decrease in the polymyxin B susceptibility of these strains, which could be restored with the cloned pmrAB genes from the mutants but not from the wild type. Reverse transcription-quantitative PCR (RT-qPCR) analysis also showed a correlation between the expression of pmrC and polymyxin B resistance. Characterization of lipid A species from the mutant strains, by thin-layer chromatography and mass spectrometry, indicated that the addition of phosphoethanolamine to lipid A correlated with resistance. This addition is performed in Salmonella enterica serovar Typhimurium by the product of the pmrC gene, which is a homolog of the pmrC gene from Acinetobacter. Knockout of this gene in the mutant R2 [pmrB(T235I)] reversed resistance as well as phosphoethanolamine modification of lipid A. These results demonstrate that specific alterations in the sequence of the pmrCAB operon are responsible for resistance to polymyxins in A. baumannii.
Acinetobacter baumannii, lipid A, mass spectrometry, phosphoethanolamine, Polymyxin B, pmrCAB
NCBI PubMed ID: 21646482Journal NLM ID: 0315061Correspondence: bob
cmdr.ubc.ca
Institutions: Centre for Microbial Diseases and Immunity Research, 232-2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada, Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, Texas 787122, Department of Molecular Biology and Biochemistry, Georgia Health Sciences University, Augusta, Georgia 30912
Methods: DNA sequencing, TLC, MALDI-TOF MS, genetic methods, biochemical methods
The publication contains the following compound(s):
- Compound ID: 9363
|
Lau-(1-3)-3HOLau-(1-3)-+ 3HOMyr-(1-2)-+
| |
3HOMyr-(1-3)-3HOLau-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P
| |
P-4)-+ 3HOLau-(1-3)-+ |
Show graphically |
Structure type: oligomer
; 1729.12
Compound class: lipid A
- Compound ID: 9364
|
Lau-(1-3)-3HOMyr-(1-2)-+
|
Lau-(1-3)-3HOLau-(1-3)-+ |
| |
3HOMyr-(1-3)-3HOLau-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P
| |
P-4)-+ 3HOLau-(1-3)-+ |
Show graphically |
Structure type: oligomer
; 1911.29
Compound class: lipid A
- Compound ID: 9365
|
Lau-(1-3)-3HOMyr-(1-2)-+
|
Lau-(1-3)-3HOLau-(1-3)-+ |
| |
3HOMyr-(1-3)-3HOLau-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1---P---P---1)-EtN
| |
P-4)-+ 3HOLau-(1-3)-+ |
Show graphically |
Structure type: oligomer
; 2034.30
Compound class: lipid A
- Compound ID: 9366
|
Lau-(1-3)-3HOMyr-(1-2)-+
|
3HOMyr-(1-3)-3HOLau-(1-2)-+ |
| |
EtN-(1---P---P---4)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1---P---P---1)-EtN
| |
Lau-(1-3)-3HOLau-(1-3)-+ 3HOLau-(1-3)-+ |
Show graphically |
Structure type: oligomer
; 2057.30
Compound class: lipid A
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