Due to its resistance to many antibiotics, methicillin-resistant Staphylococcus aureus (MRSA) have become a worldwide health problem creating the urgent necessity of developing new drugs against this pathogen. In this sense, one approach is to search for inhibitors of important enzymes in its metabolism. According to this, the shikimate pathway is an important metabolic route in bacteria and its enzymes are considered as great targets for the development of new antibiotic drugs. One of these enzymes is the shikimate dehydrogenase that catalyzes the reversal reduction from 3-dehydroshikimate to shikimate using NADPH as cofactor. In this work, four new compounds were found capable of inhibiting the shikimate dehydrogenase (SDH) from S. aureus (SaSDH) activity. A detailed kinetic characterization showed that the most potent inhibitor presented a Ki of 8 and 10 μM with respect to shikimate and NADP+ , respectively, and a mixed partial inhibition mechanism for both substrates. Molecular dynamics studies revealed that the four inhibitors perturb the structure of SaSDH affecting important domains. Toxicological and physicochemical parameters indicated that these compounds can be considered as potential drugs. Therefore, these compounds are good hits that will help in the process to obtain a new drug against MRSA.
Keywords: MRSA; drug design; enzyme kinetics; molecular dynamic; shikimate dehydrogenase.
© 2019 John Wiley & Sons A/S.