Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval
Single substitutions or combinations of them alter the hydrolytic activity towards specific β-lactam-antibiotics and β-lactamase inhibitors of TEM-β-lactamases. The sequences and phenotypic classification of allelic TEM variants, as provided by the NCBI National Database of Antibiotic Resistant Orga...
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MDPI AG
2021-08-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/9/8/1726 |
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| author | Sara Madzgalla Helena Duering Jana C. Hey Svetlana Neubauer Karl-Heinz Feller Ralf Ehricht Mathias W. Pletz Oliwia Makarewicz |
| author_facet | Sara Madzgalla Helena Duering Jana C. Hey Svetlana Neubauer Karl-Heinz Feller Ralf Ehricht Mathias W. Pletz Oliwia Makarewicz |
| author_sort | Sara Madzgalla |
| collection | DOAJ |
| description | Single substitutions or combinations of them alter the hydrolytic activity towards specific β-lactam-antibiotics and β-lactamase inhibitors of TEM-β-lactamases. The sequences and phenotypic classification of allelic TEM variants, as provided by the NCBI National Database of Antibiotic Resistant Organisms, does not attribute phenotypes to all variants. Some entries are doubtful as the data assessment differs strongly between the studies or no data on the methodology are provided at all. This complicates mathematical and bioinformatic predictions of phenotypes that rely on the database. The present work aimed to prove the role of specific substitutions on the resistance phenotype of TEM variants in, to our knowledge, the most extensive mutagenesis study. In parallel, the predictive power of extrapolation algorithms was assessed. Most well-known substitutions with direct impact on the phenotype could be reproduced, both mathematically and experimentally. Most discrepancies were found for supportive substitutions, where some resulted in antagonistic effects in contrast to previously described synergism. The mathematical modelling proved to predict the strongest phenotype-relevant substitutions accurately but showed difficulties in identifying less prevalent but still phenotype transforming ones. In general, mutations increasing cephalosporin resistance resulted in increased sensitivity to β-lactamase inhibitors and vice versa. Combining substitutions related to cephalosporin and β-lactamase inhibitor resistance in almost all cases increased BLI susceptibility, indicating the rarity of the combined phenotype. |
| first_indexed | 2024-03-10T08:34:23Z |
| format | Article |
| id | doaj.art-9a768625123a48e9a8d61daa89b9f3fd |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-10T08:34:23Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-9a768625123a48e9a8d61daa89b9f3fd2023-11-22T08:47:57ZengMDPI AGMicroorganisms2076-26072021-08-0198172610.3390/microorganisms9081726Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental ApprovalSara Madzgalla0Helena Duering1Jana C. Hey2Svetlana Neubauer3Karl-Heinz Feller4Ralf Ehricht5Mathias W. Pletz6Oliwia Makarewicz7Institute for Infectious Disease and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, GermanyInstitute for Infectious Disease and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, GermanyInstitute for Infectious Disease and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, GermanyInstitute for Infectious Disease and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, GermanyInfectoGnostics Research Campus, 07743 Jena, GermanyInfectoGnostics Research Campus, 07743 Jena, GermanyInstitute for Infectious Disease and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, GermanyInstitute for Infectious Disease and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, GermanySingle substitutions or combinations of them alter the hydrolytic activity towards specific β-lactam-antibiotics and β-lactamase inhibitors of TEM-β-lactamases. The sequences and phenotypic classification of allelic TEM variants, as provided by the NCBI National Database of Antibiotic Resistant Organisms, does not attribute phenotypes to all variants. Some entries are doubtful as the data assessment differs strongly between the studies or no data on the methodology are provided at all. This complicates mathematical and bioinformatic predictions of phenotypes that rely on the database. The present work aimed to prove the role of specific substitutions on the resistance phenotype of TEM variants in, to our knowledge, the most extensive mutagenesis study. In parallel, the predictive power of extrapolation algorithms was assessed. Most well-known substitutions with direct impact on the phenotype could be reproduced, both mathematically and experimentally. Most discrepancies were found for supportive substitutions, where some resulted in antagonistic effects in contrast to previously described synergism. The mathematical modelling proved to predict the strongest phenotype-relevant substitutions accurately but showed difficulties in identifying less prevalent but still phenotype transforming ones. In general, mutations increasing cephalosporin resistance resulted in increased sensitivity to β-lactamase inhibitors and vice versa. Combining substitutions related to cephalosporin and β-lactamase inhibitor resistance in almost all cases increased BLI susceptibility, indicating the rarity of the combined phenotype.https://www.mdpi.com/2076-2607/9/8/1726antimicrobial resistanceGram-negative bacteriamolecular diagnosticsextended-spectrum beta-lactamasesbeta-lactamase-inhibitor |
| spellingShingle | Sara Madzgalla Helena Duering Jana C. Hey Svetlana Neubauer Karl-Heinz Feller Ralf Ehricht Mathias W. Pletz Oliwia Makarewicz Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval Microorganisms antimicrobial resistance Gram-negative bacteria molecular diagnostics extended-spectrum beta-lactamases beta-lactamase-inhibitor |
| title | Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval |
| title_full | Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval |
| title_fullStr | Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval |
| title_full_unstemmed | Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval |
| title_short | Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval |
| title_sort | assessment of phenotype relevant amino acid residues in tem β lactamases by mathematical modelling and experimental approval |
| topic | antimicrobial resistance Gram-negative bacteria molecular diagnostics extended-spectrum beta-lactamases beta-lactamase-inhibitor |
| url | https://www.mdpi.com/2076-2607/9/8/1726 |
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