Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the number of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has spread worldwide. To unlock this problem, the use of an 'antibiotic adjuvant' in combination with an antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those compounds that are already in clinical development, namely β-lactamase inhibitors.
Infections caused by resistant bacteria are nowadays too common, and some pathogens have even become resistant to multiple types of antibiotics, in which case few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy "antibiotic + inhibitor of resistance". These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clinical use. Three main types of compounds have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; (iii) efflux pump inhibitors. This Perspective is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-negative bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems, and monobactams), by the production of βlactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.
Shikimate kinase (SK) is an essential enzyme in several pathogenic bacteria and does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Based on these studies several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 Å. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136, and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs.
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