scholarly journals Inferring the selection window in antimicrobial resistance using deep mutational scanning data and biophysics-based fitness models

2017 ◽  
Author(s):  
Pouria Dasmeh ◽  
Anh-Tien Ton ◽  
Caroline Quach ◽  
Adrian W.R. Serohijos
Keyword(s):  
Antimicrobial Resistance ◽  
Genetic Parameters ◽  
Catalytic Efficiency ◽  
Single Step ◽  
Mutant Selection ◽  
Selection Window ◽  
Low Levels ◽  
Lower Limits ◽  
Selection Of

AbstractMutant-selection window (MSW) hypothesis in antimicrobial resistance implies a range for antimicrobial concentration that promotes selection of single-step resistant mutants. Since the inception and experimental verification, MSW has been at the forefront of strategies to minimize development of antimicrobial resistance (AR). Setting the upper and lower limits of MSW requires an understanding of the dependence of selection coefficient of arising mutations to antimicrobial concentration. In this work, we employed a biophysics-based and experimentally calibrated fitness model to estimate MSW in the case of Ampicillin and Cefotaxime resistance in E.coli TEM-1 beta lactamase. In line with experimental observations, we show that selection is active at very low levels of antimicrobials. Furthermore, we elucidate the dependence of MSW to catalytic efficiency of mutants, fraction of mutants in the population and discuss the role of population genetic parameters such as population size and mutation rate. Altogether, our analysis and formalism provide a predictive model of MSW with direct implications in the design of dosage strategies.

scholarly journals Assessment of genetic diversity and estimation of genetic parameters for remobilization related traits of wheat under drought conditions

Genetika ◽  
2016 ◽  
Vol 48 (1) ◽  
pp. 139-149
Author(s):  
Ezatollah Farshadfar ◽  
Reza Amiri
Keyword(s):  
Dry Matter ◽  
Genetic Parameters ◽  
Predominant Role ◽  
Genetic Potential ◽  
Cropping Season ◽  
Additive Gene ◽  
Genetic Techniques ◽  
Selection Of ◽  
Kernel Yield

In order to evaluate genetic variability and estimation of remobilization related traits in wheat using biometrical genetic techniques an experiment was conducted in a randomized complete blocks design with three replicates under post-anthesis drought stress conditions in the Campus of Agriculture and Natural Resources, Razi University, Kermanshah, Iran during 2011-2012 cropping season. The results of analysis of variance showed significant differences between the genotypes for all studied traits except current photosynthesis (CP) and current photosynthesis share into kernel yield (CPSKY). High genetic gain and broad sense heritability estimates were observed for penultimate remobilization share into kernel yield (PenRSKY) and internodes remobilization share into kernel yield (IRSKY) indicating high genetic potential, low effect of environment and predominant role of additive gene effect on their expression. Spike dry matter remobilization (SDMR), spike dry matter remobilization efficiency (SDMRE) and spike remobilization share into kernel yield (SRSKY) exhibited the highest phenotypic and genetic positive correlation with kernel yield (KY). Moreover, the highest genotypic and phenotypic covariance was observed between kernel yield (KY) and SDMR, CP, SDMRE and SRSKY, respectively. The highest environmental covariance was identified between kernel yield (KY), peduncle dry matter remobilization (PedDMR) and penultimate dry matter remobilization (PenDMR), respectively. High co-heritability was detected between SDMRE and PedDMR, PedDMRE and PenDMR and between peduncle remobilization share into kernel yield (PedRSKY) and internodes dry matter remobilization efficiency (IDMRE), suggesting that selection of either of the traits would simultaneously affect the others, positively.

Antimicrobial resistance: its emergence and transmission

2008 ◽  
Vol 9 (2) ◽  
pp. 115-126 ◽  
Author(s):  
Patrick Boerlin ◽  
Richard J. Reid-Smith
Keyword(s):  
Gene Transfer ◽  
Antimicrobial Resistance ◽  
Horizontal Gene Transfer ◽  
Dna Sequencing ◽  
Large Scale ◽  
Mutant Selection ◽  
The Past ◽  
New Concepts ◽  
Selection Window ◽  
Integrative Conjugative Elements

AbstractNew concepts have emerged in the past few years that help us to better understand the emergence and spread of antimicrobial resistance (AMR). These include, among others, the discovery of the mutator state and the concept of mutant selection window for resistances emerging primarily through mutations in existing genes. Our understanding of horizontal gene transfer has also evolved significantly in the past few years, and important new mechanisms of AMR transfer have been discovered, including, among others, integrative conjugative elements and ISCR(insertionsequences withcommonregions) elements. Simultaneously, large-scale studies have helped us to start comprehending the immense and yet untapped reservoir of both AMR genes and mobile genetic elements present in the environment. Finally, new PCR- and DNA sequencing-based techniques are being developed that will allow us to better understand the epidemiology of classical vectors of AMR genes, such as plasmids, and to monitor them in a more global and systematic way.

scholarly journals Influence of Inoculum Size on the Selection of Resistant Mutants of Escherichia coli in Relation to Mutant Prevention Concentrations of Marbofloxacin

2007 ◽  
Vol 51 (11) ◽  
pp. 4163-4166 ◽  
Author(s):  
Aude Ferran ◽  
Véronique Dupouy ◽  
Pierre-Louis Toutain ◽  
Alain Bousquet-Mélou
Keyword(s):  
Escherichia Coli ◽  
Bacterial Population ◽  
Inoculum Size ◽  
Pharmacodynamic Model ◽  
Initial Size ◽  
Mutant Selection ◽  
Selection Window ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT We demonstrate using an in vitro pharmacodynamic model that the likelihood of selection of Escherichia coli mutants resistant to a fluoroquinolone was increased when the initial size of the bacterial population, exposed to fluoroquinolone concentrations within the mutant selection window, was increased.

scholarly journals Synergistic Combination of Linezolid and Fosfomycin Closing Each Other’s Mutant Selection Window to Prevent Enterococcal Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Lifang Jiang ◽  
Na Xie ◽  
Mingtao Chen ◽  
Yanyan Liu ◽  
Shuaishuai Wang ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Bacterial Resistance ◽  
Selection Index ◽  
Resistance Mechanism ◽  
Mutant Selection ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants ◽  
Synergistic Combination ◽  
Selection Of

Enterococci, the main pathogens associated with nosocomial infections, are resistant to many common antibacterial drugs including β-lactams, aminoglycosides, etc. Combination therapy is considered an effective way to prevent bacterial resistance. Preliminary studies in our group have shown that linezolid combined with fosfomycin has synergistic or additive antibacterial activity against enterococci, while the ability of the combination to prevent resistance remains unknown. In this study, we determined mutant prevention concentration (MPC) and mutant selection window (MSW) of linezolid, fosfomycin alone and in combination including different proportions for five clinical isolates of Enterococcus and characterized the resistance mechanism for resistant mutants. The results indicated that different proportions of linezolid combined with fosfomycin had presented different MPCs and MSWs. Compared with linezolid or fosfomycin alone, the combination can restrict the enrichment of resistant mutants at a lower concentration. A rough positive correlation between the selection index (SI) of the two agents in combination and the fractional inhibitory concentration index (FICI) of the combination displayed that the smaller FICI of linezolid and fosfomycin, the more probable their MSWs were to close each other. Mutations in ribosomal proteins (L3 and L4) were the mechanisms for linezolid resistant mutants. Among the fosfomycin-resistant mutants, only two strains have detected the MurA gene mutation related to fosfomycin resistance. In conclusion, the synergistic combination of linezolid and fosfomycin closing each other’s MSW could effectively suppress the selection of enterococcus resistant mutants, suggesting that the combination may be an alternative for preventing enterococcal resistance. In this study, the resistance mechanism of fosfomycin remains to be further studied.

scholarly journals Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by UsingIn VitroDynamic Models

2015 ◽  
Vol 60 (3) ◽  
pp. 1208-1215 ◽  
Author(s):  
Elena N. Strukova ◽  
Yury A. Portnoy ◽  
Andrey V. Romanov ◽  
Mikhail V. Edelstein ◽  
Stephen H. Zinner ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Area Under The Curve ◽  
Mutant Selection ◽  
Content Type ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Ciprofloxacin Resistance ◽  
Resistant Mutants ◽  
Time Courses ◽  
Selection Of

There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of threeKlebsiella pneumoniaestrains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. ResistantK. pneumoniaemutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistantK. pneumoniae(AUBCM) were bell shaped. These relationships predict highly variable “antimutant” AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor ofK. pneumoniaeresistance is lower than that of the AUC24/MIC ratio.

Susceptibility and PK/PD relationships of Staphylococcus aureus strains isolated from the milk of sheep and goats with clinical mastitis to five veterinary fluoroquinolones

2017 ◽  
Vol 180 (15) ◽  
pp. 376-376 ◽  
Author(s):  
J. M. Serrano-Rodríguez ◽  
C. Cárceles-García ◽  
C. M. Cárceles-Rodríguez ◽  
M. L. Gabarda ◽  
J. M. Serrano-Caballero ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Inhibitory Concentration ◽  
Clinical Mastitis ◽  
The Other ◽  
Mutant Selection ◽  
Sheep And Goats ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Higher Doses ◽  
Selection Of

Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of veterinary fluoroquinolones as enrofloxacin, its metabolite ciprofloxacin, danofloxacin, difloxacin and marbofloxacin against Staphylococcus aureus strains (n=24) isolated from milk of sheep and goats affected by clinical mastitis were evaluated. The authors have used the MIC and MPC, as well as the pharmacokinetic-pharmacodynamic relationships in plasma and milk. MIC values were significantly different between drugs, unlike MPC values. Lower MIC values were obtained for danofloxacin and difloxacin, middle and higher values for enrofloxacin, ciprofloxacin and marbofloxacin. However, differences in MPC values were not found between drugs. At conventional doses, the AUC24/MIC and AUC24/MPC ratios were close to 30–80 hours and 5–30 hours, with exception of danofloxacin, in plasma and milk. The time inside the mutant selection window (TMSW) was close to 3–6 hours for enrofloxacin, ciprofloxacin and marbofloxacin, near to 8 hours for danofloxacin and 12–22 hours for difloxacin. From these data, the mutant selection window could be higher for danofloxacin and difloxacin compared with the other fluoroquinolones tested. The authors concluded that enrofloxacin and marbofloxacin, at conventional doses, could prevent the selection of bacterial subpopulations of S aureus, unlike danofloxacin and difloxacin, where higher doses could be used.

scholarly journals MTopGO: a tool for module identification in PPI Networks

2017 ◽  
Author(s):  
Danila Vella ◽  
Simone Marini ◽  
Francesca Vitali ◽  
Riccardo Bellazzi
Keyword(s):  
Single Step ◽  
Ppi Network ◽  
Topological Information ◽  
Network Partition ◽  
Ppi Networks ◽  
Module Detection ◽  
Informatics Tools ◽  
Go Terms ◽  
Selection Of

The increasing amount of -omics data leads to development of models to interpret and analyse them. A common approach consists in representing data as PPI Networks. These models can be very complex and informatics tools are needed to analyse them. In this abstract, we present MTopGO, an algorithm of module detection specific for PPI Network, exploiting both the network topological information and the Gene Ontology (GO) knowledge about network proteins. MTopGO output consists in a network partition, where each obtained cluster is labelled with a specific GO term describing its biological nature. In a single step, MTopGO performs a double PPI network analysis; from a topological perspective, through the individuation of a meaningful network partition and, from a biological perspective, through the selection of significant GO terms describing the biological role of network proteins.

scholarly journals MTopGO: a tool for module identification in PPI Networks

2017 ◽  
Author(s):  
Danila Vella ◽  
Simone Marini ◽  
Francesca Vitali ◽  
Riccardo Bellazzi
Keyword(s):  
Single Step ◽  
Ppi Network ◽  
Topological Information ◽  
Network Partition ◽  
Ppi Networks ◽  
Module Detection ◽  
Informatics Tools ◽  
Go Terms ◽  
Selection Of

The increasing amount of -omics data leads to development of models to interpret and analyse them. A common approach consists in representing data as PPI Networks. These models can be very complex and informatics tools are needed to analyse them. In this abstract, we present MTopGO, an algorithm of module detection specific for PPI Network, exploiting both the network topological information and the Gene Ontology (GO) knowledge about network proteins. MTopGO output consists in a network partition, where each obtained cluster is labelled with a specific GO term describing its biological nature. In a single step, MTopGO performs a double PPI network analysis; from a topological perspective, through the individuation of a meaningful network partition and, from a biological perspective, through the selection of significant GO terms describing the biological role of network proteins.

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