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

Abstract—Solving the problem of multidrug resistance currently requires the development of nonstandard 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, and 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.