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.
Highlights
The increasing development and spread of resistance to current antibiotics have turned ordinary bacterial infections into illnesses that cannot be controlled
The enzymes involved in the shikimic acid pathway are attractive targets for the development of new anti-tubercular therapies because six of the seven enzymes, the ones encoded by aroF, aroG, aroB, aroD, aroE, aroK and aroA genes, are essential for Mycobacterium tuberculosis, which is the causative agent of tuberculosis [17]
Despite the recognized need for new antibiotics, only two new classes have been brought to the market in the last three decades
Summary
The increasing development and spread of resistance to current antibiotics have turned ordinary bacterial infections into illnesses that cannot be controlled. The European Centre for Disease Prevention and Control (ECDC) estimates that antimicrobial resistance results each year in 25,000 deaths and related costs of over €1.5 billion in healthcare expenses and productivity losses Despite this alarming trend, research into the discovery of new antibiotics by large pharmaceutical companies has dwindled dramatically [3,4]. Targeting of new pathways will likely play an important role in the discovery of new antibiotics to combat the growing problem of antibiotic-resistant bacteria For this purpose, much attention has been devoted to the inhibition of the enzymes involved in the shikimic acid pathway in recent years. This information helps to rationalize the determinants of binding affinity for inhibitors and could provide guidelines for future inhibitor design
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