The cost of resistance to colistin in <b><i>Acinetobacter baumannii</i></b>: a proteomic perspective

Fernández‐Reyes, María José; Rodríguez-Falcón, Manuel; Chiva, Cristina; Pachón, Jerónimo; Andreu, David; Rivas, Luís

doi:10.1002/pmic.200800434

Cited by 101 publications

(90 citation statements)

References 101 publications

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“…Although they remain active against most otherwise extremely resistant A. baumannii isolates, this activity is not universal, and colistin heteroresistance has been described in A. baumannii (24), as has the development of full resistance both in vitro and in vivo (17,41). Outbreaks of polymyxin-resistant A. baumannii isolates have been reported (12,35,47). Acquired polymyxin resistance in Gram-negative bacteria is most often mediated by replacement of lipid A with aminoarabinose, which requires the products of the ugd and pbg loci and ethanolamine, mediated by pmrC.…”

Section: Colistin Resistance Is Rare Inmentioning

confidence: 99%

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

Beceiro

Llobet

Aranda

et al. 2011

Antimicrob Agents Chemother

337

290

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Colistin resistance is rare in2؉ induction conditions. pmrB gene knockout mutants of the colistin-resistant ATCC 19606 derivative showed >100-fold increased susceptibility to colistin and 5-fold decreased expression of pmrC; they also lacked the addition of phosphoethanolamine to lipid A. We conclude that the development of a moderate level of colistin resistance in A. baumannii requires distinct genetic events, including (i) at least one point mutation in pmrB, (ii) upregulation of pmrAB, and (iii) expression of pmrC, which lead to addition of phosphoethanolamine to lipid A.

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Section: Colistin Resistance Is Rare Inmentioning

confidence: 99%

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

Beceiro

Llobet

Aranda

et al. 2011

Antimicrob Agents Chemother

337

290

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“…Multiple studies have reported a significant fitness cost associated with colistin resistance (Fernández-Reyes et al 2009;Ló pez-Rojas et al 2011;Rolain et al 2011), leading to the hypothesis that this fitness cost may explain the lack of widespread resistance (Ló pez- Rojas et al 2011). With other antibiotics, it has been found that the cost of resistance can be overcome either by acquiring low-cost mutations or by accumulating compensatory mutations that diminish the fitness cost (Andersson and Hughes 2010).…”

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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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“…The laboratory-derived colistin-resistant strain ATCC 19606 ColR (MIC, 16 g/ml) possesses a single nucleotide Ala227Val mutation in pmrB (32) that is adjacent to the conserved histidine at the site of phosphorylation (His228), which is critical for phosphatase activity. The final result is the addition of phosphoethanolamine to hepta-acylated lipid A (18).…”

Section: Resultsmentioning

confidence: 99%

“…The procedures for determining chromosomal DNA fragmentation and cell wall damage in situ were first assayed for control A. baumannii strains harboring known mechanisms of colistin resistance. These were laboratory isogenic strains derived from susceptible strains from the American Type Culture Collection (ATCC; Manassas, VA), ATCC 19606 ColS (MIC, 0.25 g/ml), ATCC 19606 ColR (MIC, 16 g/ ml), ATCC 19606 ColR lpxA (MIC, 32 to 64 g/ml), and ATCC 19606 ColR lpxD (MIC, Ͼ64 g/ml) (18,32,33).…”

Section: Methodsmentioning

confidence: 99%

Rapid Determination of Colistin Resistance in Clinical Strains of Acinetobacter baumannii by Use of the Micromax Assay

et al. 2013

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Colistin is an old antibiotic which has been used as a therapeutic option for carbapenem-and multidrug-resistant Gram-negative bacteria, like Acinetobacter baumannii. This pathogen produces life-threatening infections, mainly in patients admitted to intensive care units. Rapid detection of resistance to colistin may improve patient outcomes and prevent the spread of resistance. For this purpose, Micromax technology was evaluated in four isogenic A. baumannii strains with known mechanisms of resistance to colistin and in 66 isolates (50 susceptible and 16 resistant). Two parameters were determined, DNA fragmentation and cell wall damage. To assess DNA fragmentation, cells trapped in a microgel were incubated with a lysing solution to remove the cell wall, and the released nucleoids were visualized under fluorescence microscopy. Fragmented DNA was observed as spots that diffuse from the nucleoid. To assess cell wall integrity, cells were incubated with a lysis solution which removes only weakened cell walls, resulting in nucleoid release exclusively in affected cells. A dose-response relationship was demonstrated between colistin concentrations and the percentages of bacteria with DNA fragmentation and cell wall damage, antibiotic effects that were delayed and less frequent in resistant strains. Receiver operating characteristic (ROC) curves demonstrated that both DNA fragmentation and cell wall damage were excellent parameters for identifying resistant strains. Obtaining <11% of bacteria with cell wall damage after incubation with 0.5 g/ml colistin identified resistant strains of A. baumannii with 100% sensitivity and 96% specificity. Results were obtained in 3 h 30 min. This is a simple, rapid, and accurate assay for detecting colistin resistance in A. baumannii, with strong potential value in critical clinical situations.

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The cost of resistance to colistin in Acinetobacter baumannii: a proteomic perspective

Cited by 101 publications

References 101 publications

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

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

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

Rapid Determination of Colistin Resistance in Clinical Strains of Acinetobacter baumannii by Use of the Micromax Assay

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