Indications of carbapenem resistance evolution through heteroresistance as an intermediate stage in Acinetobacter baumannii after carbapenem administration

Superti, Silvana; Martins, Daniela de Souza; Caierão, Juliana; Soares, Fabiana da Silva; Prochnow, Taísa; Zavascki, Alexandre Prehn

doi:10.1590/s0036-46652009000200010

Cited by 13 publications

(12 citation statements)

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“…Dynamic binding interactions, such as those that occur in phosphorylation events, appear prominently in signaling pathways in health and in disease including hypertension, diabetes, HIV infection, and cancer [2,30]. Although kinases have long been considered as drug targets, compounds targeting kinases (kinase inhibitors and natural substances) have been found to be more promiscuous than originally anticipated, which can potentially lead to side effects [31]. It is important to identify potential phosphorylation partners of kinases in order to assess its range of impact on the flow of signals and metabolites along cellular pathways.…”

Section: Discussionmentioning

confidence: 99%

Modular composition predicts kinase/substrate interactions

Liu

Tözeren

2010

BMC Bioinformatics

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BackgroundPhosphorylation events direct the flow of signals and metabolites along cellular protein networks. Current annotations of kinase-substrate binding events are far from complete. In this study, we scanned the entire human protein sequences using the PROSITE domain annotation tool to identify patterns of domain composition in kinases and their substrates. We identified statistically enriched pairs of strings of domains (signature pairs) in kinase-substrate couples presented in the 2006 version of the PTM database.ResultsThe signature pairs enriched in kinase - substrate binding interactions turned out to be highly specific to kinase subtypes. The resulting list of signature pairs predicted kinase-substrate interactions in validation dataset not used in learning with high statistical accuracy.ConclusionsThe method presented here produces predictions of protein phosphorylation events with high accuracy and mid-level coverage. Our method can be used in expanding the currently available drafts of cell signaling pathways and thus will be an important tool in the development of combination drug therapies targeting complex diseases.

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Section: Discussionmentioning

confidence: 99%

Modular composition predicts kinase/substrate interactions

Liu

Tözeren

2010

BMC Bioinformatics

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“…Similarly, elevated expression of the ␤-lactamase gene in resistant subpopulations compared to native populations was detected in Klebsiella pneumoniae isolates heteroresistant to meropenem (40) and in imipenem-heteroresistant A. baumannii (91). However, certain carbapenem-heteroresistant A. baumannii isolates were carbapenemase negative, suggesting that other factors are involved in the phenomenon (90). Differences in transcriptional levels may also underlie heteroresistance to carbapenems in P. aeruginosa; compared to the native populations, the resistant subpopulations had significantly increased transcription levels of the mexB and mexY genes, whose protein products are involved in multidrug efflux, and decreased expression of the oprD gene, encoding an outer membrane porin (57).…”

Section: Heteroresistance To ␤-Lactamsmentioning

confidence: 95%

“…Disc diffusion assays (3,14,18,55,(86)(87)(88)(89)(90)(91)(92) and Etest strips have been used to detect heteroresistance as recommended for traditional in vitro susceptibility testing (6,15,18,50,63,64,66,68,71,73,76,80,86,(88)(89)(90)(91)(93)(94)(95)(96)(97)(98)(99)(100)(101). Special Etest strips were developed for glycopeptide resistance detection (GRD Etest) (69,74,75,81,102).…”

Section: Disc Diffusion and Etest Assaysmentioning

confidence: 99%

“…For example, colistin treatment of a patient with meningitis due to a colistin-heteroresistant A. baumannii strain resulted in selection of colistin-resistant derivatives (149). More-over, A. baumannii isolates transitioned in vivo from susceptibility to full resistance to carbapenems, with heteroresistance as an intermediate stage, due to administration of meropenem (90). Meropenem pressure can produce meropenem-heteroresistant subpopulations of A. baumannii that may be selected for by suboptimal therapeutic drug dosages, giving rise to highly resistant strains (39).…”

Section: Selection For the More Resistant Cells In The Populationmentioning

confidence: 99%

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Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity

2015

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SUMMARY “Heteroresistance” describes a phenomenon where subpopulations of seemingly isogenic bacteria exhibit a range of susceptibilities to a particular antibiotic. Unfortunately, a lack of standard methods to determine heteroresistance has led to inappropriate use of this term. Heteroresistance has been recognized since at least 1947 and occurs in Gram-positive and Gram-negative bacteria. Its clinical relevance may be considerable, since more resistant subpopulations may be selected during antimicrobial therapy. However, the use of nonstandard methods to define heteroresistance, which are costly and involve considerable labor and resources, precludes evaluating the clinical magnitude and severity of this phenomenon. We review the available literature on antibiotic heteroresistance and propose recommendations for definitions and determination criteria for heteroresistant bacteria. This will help in assessing the global clinical impact of heteroresistance and developing uniform guidelines for improved therapeutic outcomes.

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“…Phenotypic heterogeneous resistance (PHR) to antimicrobials in A. baumannii has been described for colistin and carbapenems and is detected by visualisation of colonies within the zone of inhibition around disks or Etest strips [3][4][5][6][7][8][9][10][11]. These colonies may represent truly resistant subpopulations containing stable changes in their genome (mutations or genes) associated with resistance to antimicrobials (heteroresistance), or they may be related to subpopulations able to persist in a latent state in the presence of antimicrobials (bacterial persistence) [12,13].…”

Section: Introductionmentioning

confidence: 99%