Bacterial cell wall components as targets for searching for new antibacterial compounds. Methods of study

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Abstract

In the current world, antibiotic resistance is one of the most serious threats to both human health and food security. Finding new ways to prevent and overcome the formation of pathogen resistance to antibiotics is an extremely important and urgent task of modern medical science. All bacteria, except mycoplasmas, have a cell wall in which various enzymes, receptors, transporters, channels and antigens are localized. This review is devoted to describing the structure of the major elements of bacterial cell walls and enzymes involved in their biosynthesis and used as molecular targets for screening and selection of new effective antibiotics. Special attention is paid to methods for studying the functional activity and inhibition of these targets. In addition, the review describes the functional characteristics of pore-forming proteins from the outer membrane of Gram-negative bacteria and the molecular mechanisms of antibiotic penetration through porin channels. Analysis of the structure and functional features of targets of different classes of antibiotics is the basis for developing new strategies to overcome bacterial resistance.

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About the authors

E. A. Chingizova

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences

Author for correspondence.
Email: martyyas@mail.ru
Russian Federation, Vladivostok, 690022

O. D. Novikova

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences

Email: martyyas@mail.ru
Russian Federation, Vladivostok, 690022

O. Y. Portnyagina

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences

Email: martyyas@mail.ru
Russian Federation, Vladivostok, 690022

D. L. Aminin

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences

Email: martyyas@mail.ru
Russian Federation, Vladivostok, 690022

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Supplementary files

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1. JATS XML
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2. Fig. 1. Biosynthesis of peptidoglycan precursors in the cytoplasm, catalyzed by enzymes of the Mur family [26] (Creative Commons Attribution License, with modifications).

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3. Fig. 2. Schematic diagram of the determination of murein ligase activity by scintillation close range assay (SPA) using polystyrene microspheres as a ligand support.

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4. Fig. 3. Scheme of action of transglycosylase and transpeptidase.

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5. Fig. 4. The principle of action of sortase A [113] (Creative Commons Attribution License, with modifications).

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6. Fig. 5. The structure of teichoic and lipoteichoic acids and a schematic representation of their localization in the cell membrane.

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7. Fig. 6. Biosynthesis of teichoic acid. TA is sequentially synthesized by a series of Tar enzymes on a bactoprenyl phosphate carrier on the inner surface of the cell membrane and transported to the outer surface where it cross-links to peptide glycan [132] (Creative Commons Attribution License, with modifications).

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8. Fig. 7. Scheme of biosynthesis of lipoteichoic acid type I (LTA I), using Staphylococccus aureus as an example. a — The glycolipid anchor diglucosyldiacylglycerol (Glc2DAG) is synthesized from diacylglycerol (DAG) and uridine diphosphate glucose (UDP-Glc) by diglucosyldiacylglycerol synthase (YpfP) and transported to the outer side of the membrane by transferase LtaA, 1,3-diglycerophosphate (DGP) is cleaved from phosphatidylglycerol (PG) and attached to Glc2DAG, the polymerization is catalyzed by the enzyme LtaS. Elongation of the polymer leads to the release of DAG, the enzyme DgkB initiates its recycling. b — Alternative pathway of polymerization of the LTA main chain. Phosphatidylglycerol (PG) serves as an acceptor, and LtaS transferase is required to transfer DGP and polyglycerophosphate (PGP) to Glc2DAG as an acceptor.

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9. Fig. 8. Lipopolysaccharides have different structural regions responsible for different functions.

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10. Fig. 9. Theoretical model of the spatial structure of the OmpF porin from Y. pseudotuberculosis. a — Top view of the OmpF trimer; b — side view of the OmpF trimer. The localization of tryptophan (a) and tyrosine (b) residues is shown. Amino acid residues are shown in a spherical representation. The figure was created using the MOE program (https://www.chemcomp.com).

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11. Fig. 10. Spatial organization of probable YpOmpF complexes with norfloxacin mono- and dihydrochloride. 3D structure of YpOmpF porin homotrimer, two subunits are shown as a molecular surface, one as a ribbon diagram, lipids and aqueous environment are removed for clarity. NfH+1 (a) and Nf2H+2 (b) molecules in two binding sites are shown in ball representation, in trans position in pink and blue, in cis position in yellow and green. Accordingly, the amino acid residues surrounding them are shown in rod representation. The callouts show 2D diagrams of intermolecular interactions of NfH+1 (a) and Nf2H+2 (b) in both binding sites [210].

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