History of the Creation of a New Generation of Antibiotics of the Group of Polycyclic Glycopeptides

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Increased resistance to polycyclic glycopeptide antibiotics has become a serious problem for chemotherapy of infections caused by resistant Gram-positive bacteria. Chemical modification of known natural antibiotics is the main direction in the creation of new generation anti-infective drugs. Over the past two decades, a series of hydrophobic glycopeptide analogues active against resistant strains of Gram-positive bacteria have been developed, three of which – oritavancin, telavancin, and dalbavancin – were approved by the US Food and Drug Administration (FDA) in 2013–2014 for the treatment of infections caused by sensitive and resistant strains of staphylococci and enterococci. It has been established that hydrophobic derivatives of glycopeptides can act on resistant strains of bacteria by a mechanism that does not allow binding to the modified target of resistant bacteria. Understanding the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve fundamental results. The possibility of using semi-synthetic glycopeptide analogues in the fight against viral infections caused by envelope viruses is also considered. The review outlines the main ways of chemical design in creating a new generation of glycopeptide antibiotics that overcome resistance to Gram-positive pathogens, and the mechanisms of their action.

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Sobre autores

E. Olsufyeva

Gause Institute of New Antibiotics

Autor responsável pela correspondência
Email: eolsufeva@list.ru
Rússia, Moscow, 119021

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2. Fig. 1. Structures of natural glycopeptides: vancomycin (1), teicoplanin A2-2 (2) and eremomycin (3).

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3. Fig. 2. Interaction of vancomycin aglycone (4) with Ac2-Lys-D-Ala-D-Ala peptide (Ka ~105 M-1) (a) and Ac2-Lys-D-Ala-D-Lac depsipeptide (Ka ~102 M-1) (b). Schematic of the mechanism of sensitivity (S) and resistance (R) of E. spp. to vancomycin (1) (c). Dotted lines show hydrogen bonds, arrows - repulsion between oxygen atoms of the antibiotic molecule and the target.

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4. Fig. 3. Main pathways of chemical transformation of glycopeptide antibiotics on the example of eremomycin (3). Coloured arrows show modifications of the whole molecule, black arrows show partial degradation reactions.

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5. Fig. 4. Stewart-Brigleb model of the eremomycin (3) complex (coloured atoms) with Ac2-L-Lys-D-Ala-D-Ala ligand (white atoms).

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6. Fig. 5. Structures of eremomycin derivatives (3a-c) modified by AK1 (a) and by AK1 and AK3 (b). Bz - benzyl.

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7. Fig. 6. Transformations of glycopeptide aglycones at amino acid residues AK1 and AK1/AK3 (compounds 5a-c and 6b-d) and devoid of AK1 and AK3 (compounds 6a and 6e).

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8. Fig. 7. Abbreviated scheme for the preparation of the key intermediate 4,5-thioanalogue of the aglycone vancomycin (7a).

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9. Fig. 8. Structures of the 4,5-thioanalogue aglycone of vancomycin (7a) and, respectively, its aminomethylene- (NH2-CH2-) and amidino derivatives (NH(C=NH)-) (7b, 7c).

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10. Fig. 9. Interaction of vancomycin derivative (7b) with Ac2-Lys-D-Ala-D-Lac depepsipeptide (Ka = 5 × 103 M-1) (a) and with Ac2-Lys D-Ala-D-Ala peptide (Ka = 4.8 × 103 M-1) (b).

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11. Fig. 10. Model of the interaction of vancomycin derivative (7c) with Ac2-Lys-D-Ala-D-Lac depepsipeptide (Ka = 6.9 × 104 M-1) (a) and Ac2-Lys-D-Ala-D-Ala peptide (Ka = 7.3 × 104 M-1) (b).

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12. Fig. 11. Structures of eremomycin derivatives (3a, 3b), chloreremomycin (13) and its derivative oritavancin (13a).

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13. Fig. 12. Structures of the N'-acyl derivatives of vancomycin (1a) and dalbavancin (14).

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14. Fig. 13. Structures of the Mannich base-type derivatives telavancin (1b) and eremomycin (3d).

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15. Fig. 14. Formula of compounds (3d-f) given in Table 1.

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16. Fig. 15. Structures of the carboxamide analogues of eremomycin (3g-3m) and de-Cl-F-oritavancin (13b).

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17. Fig. 16. REDOR models of interaction of 19F-containing analogues of eremomycin (3j) (a) and chloreremomycin (13b) (b) with peptidoglycan fragments of intact Staphylococcus aureus cells with the peptide leg D-iso-Gln-L-Ala and, respectively, with the -(Gly)5- bridge. Straight blue arrow indicates 19F-containing hydrophobic radicals (highlighted in green) of antibiotics.

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18. Fig. 17. A putative model of the mechanisms of action of vancomycin (1) (a) and glycopeptide derivatives containing a hydrophobic substituent (3d-3j, as well as 3l, 13a, 13b) (b). Inhibition by vancomycin (1) of the transpeptidation step in case (a) is negligible, so it is not shown.

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19. Fig. 18. Vancomycin derivatives (1c, 1d) containing a hydrophobic radical and a positively charged group.

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20. Fig. 19. Model of eremomycin homodimer formation (3). R1-R7 are side radicals of the peptide cortex of the antibiotic. The dotted line indicates hydrogen bonds between HN- and CO-groups of peptide chains of two antibiotic molecules.

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21. Fig. 20. Model scheme showing the proximity of 15N-amide groups of eremomycin (3m) to 13C atoms of the peptide fragment of peptidoglycan of intact S. aureus cell measured by REDOR method. The dotted line shows the distances in Å.

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22. Fig. 21. Derivatives of the aglycones eremomycin (5d, e) and teicoplanin 6e-h, which have antiviral activity, and 5d, 6f-h, which inhibit kinase activity.

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23. Fig. 22. Structures of cefilavancin (1c) and conjugates of eremomycin with azithromycin (3n) and with 3,6'-di-Bz-oxycarbonylcanamycin A (3o).

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