Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies
For some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of gl...
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MDPI AG
2021-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/2/83 |
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| author | László Izsépi Réka Erdei Anna N. Tevyashova Natalia E. Grammatikova Andrey E. Shchekotikhin Pál Herczegh Gyula Batta |
| author_facet | László Izsépi Réka Erdei Anna N. Tevyashova Natalia E. Grammatikova Andrey E. Shchekotikhin Pál Herczegh Gyula Batta |
| author_sort | László Izsépi |
| collection | DOAJ |
| description | For some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of glycopeptide antibiotics is essentially the binding of peptidoglycan cell-wall fragments terminating in the <span style="font-variant: small-caps;">d</span>-Ala-<span style="font-variant: small-caps;">d</span>-Ala sequence to the carboxylate anion binding pocket of the antibiotic. Dimerization of these antibiotics in aqueous solution was shown to persist and even to enhance the antibacterial effect in a co-operative manner. Some works based on solid state (ss) Nuclear Magnetic Resonance (NMR) studies questioned the presence of dimers under the conditions of ssNMR while in a few cases, higher-order oligomers associated with contiguous back-to-back and face-to-face dimers were observed in the crystal phase. However, it is not proved if such oligomers persist in aqueous solutions. With the aid of <sup>15</sup>N-labelled eremomycin using <sup>15</sup>N relaxation and diffusion NMR methods, we observed tetramers and octamers when the <i>N</i>-Ac-<span style="font-variant: small-caps;">d</span>-Ala-<span style="font-variant: small-caps;">d</span>-Ala dipeptide was added. To the contrary, the <i>N</i>-Ac-<span style="font-variant: small-caps;">d</span>-Ala or (<i>N</i>-Ac)<sub>2</sub>-<span style="font-variant: small-caps;">l</span>-Lys-<span style="font-variant: small-caps;">d</span>-Ala-<span style="font-variant: small-caps;">d</span>-Ala tripeptide did not induce higher-order oligomers. These observations are interesting examples of tailored supramolecular self-organization. New antimicrobial tests have also been carried out with these self-assemblies against MRSA and VRE (resistant) strains. |
| first_indexed | 2024-03-09T03:55:16Z |
| format | Article |
| id | doaj.art-1ab6d93b230545b1af7ec8d559651007 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T03:55:16Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-1ab6d93b230545b1af7ec8d5596510072023-12-03T14:21:01ZengMDPI AGPharmaceuticals1424-82472021-01-011428310.3390/ph14020083Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial StudiesLászló Izsépi0Réka Erdei1Anna N. Tevyashova2Natalia E. Grammatikova3Andrey E. Shchekotikhin4Pál Herczegh5Gyula Batta6Doctoral School of Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1., HungaryDepartment of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1., HungaryGause Institute of New Antibiotics, 11 B. Pirogovskaya, 119021 Moscow, RussiaGause Institute of New Antibiotics, 11 B. Pirogovskaya, 119021 Moscow, RussiaGause Institute of New Antibiotics, 11 B. Pirogovskaya, 119021 Moscow, RussiaDepartment of Pharmaceutical Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1., HungaryDepartment of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1., HungaryFor some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of glycopeptide antibiotics is essentially the binding of peptidoglycan cell-wall fragments terminating in the <span style="font-variant: small-caps;">d</span>-Ala-<span style="font-variant: small-caps;">d</span>-Ala sequence to the carboxylate anion binding pocket of the antibiotic. Dimerization of these antibiotics in aqueous solution was shown to persist and even to enhance the antibacterial effect in a co-operative manner. Some works based on solid state (ss) Nuclear Magnetic Resonance (NMR) studies questioned the presence of dimers under the conditions of ssNMR while in a few cases, higher-order oligomers associated with contiguous back-to-back and face-to-face dimers were observed in the crystal phase. However, it is not proved if such oligomers persist in aqueous solutions. With the aid of <sup>15</sup>N-labelled eremomycin using <sup>15</sup>N relaxation and diffusion NMR methods, we observed tetramers and octamers when the <i>N</i>-Ac-<span style="font-variant: small-caps;">d</span>-Ala-<span style="font-variant: small-caps;">d</span>-Ala dipeptide was added. To the contrary, the <i>N</i>-Ac-<span style="font-variant: small-caps;">d</span>-Ala or (<i>N</i>-Ac)<sub>2</sub>-<span style="font-variant: small-caps;">l</span>-Lys-<span style="font-variant: small-caps;">d</span>-Ala-<span style="font-variant: small-caps;">d</span>-Ala tripeptide did not induce higher-order oligomers. These observations are interesting examples of tailored supramolecular self-organization. New antimicrobial tests have also been carried out with these self-assemblies against MRSA and VRE (resistant) strains.https://www.mdpi.com/1424-8247/14/2/83glycopeptideresistanceeremomycindimeroligomer<i>N</i>-Ac-<span style="font-variant: small-caps">d</span>-Ala-<span style="font-variant: small-caps">d</span>-Ala |
| spellingShingle | László Izsépi Réka Erdei Anna N. Tevyashova Natalia E. Grammatikova Andrey E. Shchekotikhin Pál Herczegh Gyula Batta Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies Pharmaceuticals glycopeptide resistance eremomycin dimer oligomer <i>N</i>-Ac-<span style="font-variant: small-caps">d</span>-Ala-<span style="font-variant: small-caps">d</span>-Ala |
| title | Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies |
| title_full | Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies |
| title_fullStr | Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies |
| title_full_unstemmed | Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies |
| title_short | Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies |
| title_sort | bacterial cell wall analogue peptides control the oligomeric states and activity of the glycopeptide antibiotic eremomycin solution nmr and antimicrobial studies |
| topic | glycopeptide resistance eremomycin dimer oligomer <i>N</i>-Ac-<span style="font-variant: small-caps">d</span>-Ala-<span style="font-variant: small-caps">d</span>-Ala |
| url | https://www.mdpi.com/1424-8247/14/2/83 |
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