Enzymes of ADP-Heptose Biosynthesis as Targets for the Creation of Broad-Spectrum Antibacterial Drugs

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Abstract

Solving the problem of multidrug resistance currently requires the development of non-standard approaches, since the potential for creating new antibiotics is almost exhausted. Controlling the metabolism of a pathogen in order to increase its susceptibility to antibacterial therapy is considered the most promising area of research for the creation of new combination drugs. In recent years, the number of studies devoted to investigation the role of the biosynthesis of the cell wall component ADP-heptose in the sensitivity of bacteria to antibiotics, as well as in the pathogenesis of bacterial infection, has increased. This review examines the main directions of scientific research in the field of use of ADP-heptose and its analogues in the treatment of bacterial infections. The exclusive role of ADP-heptose in the induction of an immune response is known, through the activation of the NF-κB signaling pathway and the synthesis of pro-inflammatory cytokines. Our latest work has shown that disruption of the synthesis of ADP-heptose and the efflux of sedoheptulose-7-phosphate from the pentose phosphate pathway induces a redox imbalance and completely disorganizes the metabolism of low molecular weight thiols such as hydrogen sulfide, cysteine, glutathione, which makes the bacterial cell extremely vulnerable to the action of antibiotics. We demonstrate that the hypersensitivity of ADP-heptose mutants to a wide range of antibiotics is explained by a new metabolic status rather than by changes in cell wall permeability. Thus, potential inhibitors of ADP-heptose biosynthesis can combine several positive qualities: an immunomodulatory effect and a powerful potentiating effect in combination with antibiotic therapy.

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T. A. Seregina

Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences

Author for correspondence.
Email: tatyana.s82@gmail.com
Russian Federation, Moscow, 119991

I. Yu. Petrushanko

Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences

Email: tatyana.s82@gmail.com
Russian Federation, Moscow, 119991

K. V. Lobanov

Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences

Email: tatyana.s82@gmail.com
Russian Federation, Moscow, 119991

R. S. Shakulov

Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences

Email: tatyana.s82@gmail.com
Russian Federation, Moscow, 119991

A. S. Mironov

Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences

Email: tatyana.s82@gmail.com
Russian Federation, Moscow, 119991

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2. Fig. 1. Cell wall structure of Gram-negative bacteria [14, Creative Commons Attribution (CC BY) licence]. ADP-heptose is the link between the polysaccharide chains of the O-antigen and the inner nucleus (ILC) [13]. The structure of LPS mutants that have lost ADP-heptose is unstable due to the absence of negatively charged phosphate groups on heptose residues, which normally stabilise the structure through interaction with positively charged ions. In addition, the cell wall of mutants that have lost ADP-heptose is characterised by increased permeability to hydrophobic compounds [15].

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3. Fig. 2. Structure of LPS of the cell wall of Gram-negative bacteria. Stages of ADP-heptose biosynthesis from sedoheptulose-7-phosphate. The gmhA, hldE, and gmhB genes are not part of the rfa operon. The subsequent steps of LPS assembly are carried out by enzymes whose genes are combined into two rfa operons. Hep I, II, III, IV are ADP-heptose residues. F - phosphate. CDO - 3-deoxy-D-manno-oct-2-ulosonic acid.

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4. Fig. 3. Purine biosynthesis as a factor modulating the sensitivity of ADP-heptose mutants. a - Metabolic scheme of the pentose phosphate pathway showing the interrelation of the processes of synthesis of ADP-heptose precursor - sedoheptulose-7-phosphate, ribose-5-phosphate and NADPH reduction. The PurR repressor regulates purine synthesis, starting with the formation of phosphoribosyl pyrophosphate, as well as the serine-glycine pathway (glyA gene), which along with the oxidative branch of the pentose phosphate pathway is the source of NADPH generation. b - Inactivation of ADP-heptose synthesis leads to a ‘deep rough’ phenotype, hypersensitivity to antibiotics and oxidative stress. Activation of purine biosynthesis in bacterial cells with impaired ADP-heptose synthesis suppresses antibiotic sensitivity and oxidative stress [44], Creative Commons Attribution (CC BY) licence. G6F - glucose-6-phosphate, F6F - fructose-6-phosphate, 3-FGA - glyceraldehyde-3-phosphate, F1,6DF - fructose-1,6-diphosphate, DGAP - dihydroxyacetone phosphate, Ru5F - ribulose-5-phosphate, R5F - ribose-5-phosphate, Xi5F - xylose-5-phosphate, C7F - sedoheptulose-7-phosphate, TGF - tetrahydrofolate, CTC - tricarboxylic acid cycle.

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