Evaluation of Antimicrobial Activity of New Mastoparan Derivatives Using QSAR and Computational Mutagenesis

Avram, Speranța; Duda-Seiman, Daniel; Borcan, Florin; Radu, Beatrice; Duda-Seiman, Corina; Mihăilescu, Dan

doi:10.1007/s10989-010-9235-7

Cited by 13 publications

(25 citation statements)

References 28 publications

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“…To avoid redundancy of independent variables and to ensure no chance correlation, the inter-correlation of the independent variables matrix was calculated according to Pearson correlation method [25][26][27] (Table 3).…”

Section: Descriptors Calculationmentioning

confidence: 99%

“…A reliable equation for structure activity relationship should possess a high correlation coefficient, low standard error of estimate prediction (SEE) [25][26][27] and the least possible number of variables. In our study the q 2 -cross validated and optimum number of PLS components (n = 4) 24 were evaluated by applying the cross-validation procedure and the Partial Least Squares (PLS) algorithm.…”

Section: Statistical Calculationsmentioning

confidence: 99%

“…In our study the q 2 -cross validated and optimum number of PLS components (n = 4) 24 were evaluated by applying the cross-validation procedure and the Partial Least Squares (PLS) algorithm. Further, multiple linear regression analysis (MLRA) 25,26 was used to generate the control criteria correlation [25][26][27] .…”

Section: Statistical Calculationsmentioning

confidence: 99%

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Section: Descriptors Calculationmentioning

confidence: 99%

Section: Statistical Calculationsmentioning

confidence: 99%

See 1 more Smart Citation

More effective dithiocarbamate derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design

Avram

Milac

Carta

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…A number of 2D QSAR studies were performed on AMPs [24,[27][28][29][30] and proved that molecular descriptors, such as the isoelectric point, hydrophobicity, weighted holistic invariant molecular index (WHIM) of amino acids, and also the contact energy between neighboring amino acids and the isotropic surface area (ISA) are critical for the antimicrobial activity of peptides. In our previous study [31] we generated 2D-QSAR models to predict the antimicrobial activity of mastoparan analogs [22] and their derivatives obtained by computational chemistry, using molecular descriptors such as molecular volume and area, and also descriptors derived directly from the amino acid sequence, or the number of acceptor and donor atoms.…”

Section: Introductionmentioning

confidence: 99%

“…Although AMPs are widely accepted as important antimicrobial compounds, there are few QSAR studies aiming at predicting their activity [24,[27][28][29][30][31]. However, these studies use 2D-QSAR methods and not 3D-QSAR-comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA).…”

Section: Introductionmentioning

confidence: 99%

Prediction of improved antimicrobial mastoparan derivatives by 3D-QSAR-CoMSIA/CoMFA and computational mutagenesis

et al. 2012

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Antimicrobial peptides are an important class of therapeutic agents used against a wide range of pathogens such as gram-negative and -positive bacteria, fungi, and viruses. The minimal inhibitory concentration at the level of the pathogen membrane is a major determinant of the pharmacokinetic behavior and, consequently, it can affect their antimicrobial activity. Here we generated quantitative structure-activity relationship models (3D-QSAR-comparative molecular field analysis/comparative molecular similarity indices analysis) using a database of 33 mastoparan analogs, antimicrobial peptides with known experimental activity, and further used these models to predict the minimal inhibitory concentration for 18 new mastoparan analogs, obtained by computational mutagenesis. We discuss two options for structural alignment of mastoparan analogs: superposition of C a trace atoms or superposition of all backbone atoms. Significant values of the cross-validated correlation q 2 (higher than 0.60) and the fitted correlation r 2 (higher than 0.90) of our models indicate that they are reliable enough for activity prediction in the case of new derivatives. This allows us to identify compounds with possibly enhanced antimicrobial activity against Bacillus subtilis, which are suggested for further experimental studies.

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Multispecies activity screening of microcin J25 mutants yields antimicrobials with increased specificity toward pathogenic Salmonella species relative to human commensal Escherichia coli

Ritter

Yang

Kaznessis

et al. 2018

Biotech & Bioengineering

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Modern large-scale agricultural practices that incorporate high density farming with subtherapeutic antibiotic dosing are considered a major contributor to the rise of antibiotic-resistant bacterial infections of humans with species of Salmonella being a leading agriculture-based bacterial infection. Microcin J25, a potent and highly stable antimicrobial peptide active against Enterobacteriaceae, is a candidate antimicrobial against multiple Salmonella species. Emerging evidence supports the hypothesis that the composition of the microbiota of the gastrointestinal tract prevents a variety of diseases by preventing infectious agents from proliferating. Reducing clearance of off-target bacteria may decrease susceptibility to secondary infection. Of the Enterobacteriaceae susceptible to microcin J25, Escherichia coli are the most abundant within the human gut. To explore the modulation of specificity, a collection of 207 mutants encompassing 12 positions in both the ring and loop of microcin J25 was built and tested for activity against Salmonella and E. coli strains. As has been found previously, mutational tolerance of ring residues was lower than loop residues, with 22% and 51% of mutations, respectively, retaining activity toward at least one target within the target organism test panel. The multitarget screening elucidated increased mutational tolerance at position G2, G3, and G14 than previously identified in panels composed of single targets. Multiple mutations conferred differential response between the different targets. Examination of specificity differences between mutants found that 30% showed significant improvements to specificity toward any of the targets. Generation and testing of a combinatorial library designed from the point-mutant study revealed that microcin J25 reduces off-target activity toward commensal human-derived E. coli isolates by 81% relative to Salmonella enterica serovar Enteritidis. These in vitro specificity improvements are likely to improve in vivo treatment efficacy by reducing clearance of commensal bacteria in the gastrointestinal tract of hosts.

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Evaluation of Antimicrobial Activity of New Mastoparan Derivatives Using QSAR and Computational Mutagenesis

Cited by 13 publications

References 28 publications

More effective dithiocarbamate derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design

More effective dithiocarbamate derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design

Prediction of improved antimicrobial mastoparan derivatives by 3D-QSAR-CoMSIA/CoMFA and computational mutagenesis

Multispecies activity screening of microcin J25 mutants yields antimicrobials with increased specificity toward pathogenic Salmonella species relative to human commensal Escherichia coli

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