Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

Abstract

Abstract:The loss of effectiveness of current antibiotics caused by the development of drug resistance has become a severe threat to public health. Current widely used antibiotics are surprisingly targeted at a few bacterial functions -cell wall, DNA, RNA, and protein biosynthesis -and resistance to them is widespread and well identified. There is therefore great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target other essential processes for bacterial survival. In the past few years a great deal of effort has been focused on the discovery of new inhibitors of the enzymes involved in the biosynthesis of aromatic amino acids, also known as the shikimic acid pathway, in which chorismic acid is synthesized. The latter compound is the synthetic precursor of L-Phe, L-Tyr, L-Phe, and other important aromatic metabolites. These enzymes are recognized as attractive targets for the development of new antibacterial agents because they are essential in important pathogenic bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori, but do not have any counterpart in human cells. This review is focused on two key enzymes of this pathway, shikimate kinase and type II dehydroquinase. An overview of the use of structure-based design and computational studies for the discovery of selective inhibitors of these enzymes will be provided. A detailed view of the structural changes caused by these inhibitors in the catalytic arrangement of these enzymes, which are responsible for the inhibition of their activity, is described.

A Three-Ring Circus: Metabolism of the Three Proteogenic Aromatic Amino Acids and Their Role in the Health of Plants and Animals

“…For Helicobacter pylori , the causative agent of gastric ulcers and a type I carcinogen, four of the seven shikimate pathway genes, aroQ, aroE, aroK , and aroC , are essential. It can be seen that SK ( aroK ) and type II DHQ ( aroD/aroQ ) are important in both tuberculosis and H. pylori infections, and therapeutics based on inhibiting these two enzymes were reviewed extensively elsewhere (González-Bello, 2016 ).…”

Flavodoxins as Novel Therapeutic Targets against Helicobacter pylori and Other Gastric Pathogens

“…The shikimic acid pathway uses erythrose-4-phosphate and phosphoenol pyruvate to produce chorismic acid, the precursor of aromatic amino acids, folate cofactors, ubiquinone, and vitamins E and K. This biosynthetic route involves four Hp essential enzymes that are absent in mammals: 3-dehydroquinate dehydratase, shikimate dehydrogenase, shikimate kinase, and chorismate synthase [30][31][32]34]. The biosynthesis of coenzyme A (CoA), an essential bacterial cofactor, is achieved with participation of phosphopantetheine adenylyltransferase (PPAT), the inactivation of which prevents bacterial viability [35,36].…”

Synthesis, biological activity and molecular modelling studies of shikimic acid derivatives as inhibitors of the shikimate dehydrogenase enzyme of Escherichia coli

“…Targeting the SA pathway has led to drug development of antibacterial agents for critical pathogenic bacteria such as the tuberculosis responsible agent Mycobacterium tuberculosis 6 and Helicobacter pylori 7 a primary causative factor for gastrointestinal illnesses. The anti-parasitic against the malaria parasite Plasmodium falciparum 8 and toxoplasmosis parasite Toxoplasma gondhii 9 , as well as one of the most widely used herbicide during the past three decades glyphosate [N-(phosphonomethyl) glycine] the active ingredient in RoundUp ® , Zero ® and Tumbleweed ® 10 , 11 .…”