ABSTRACT
One of the most widespread pathogens worldwide is methicillin-resistant Staphylococcus aureus, a bacterium that provokes severe life-threatening illnesses both in hospitals and in the community. The principal challenge lies in the resistance of MRSA to current treatments, which encourages the study of different molecular targets that could be used to develop new drugs against this infectious agent. With this goal, a detailed characterization of shikimate kinase from this microorganism (SaSK) is described. The results showed that SaSK has a Km of 0.153 and 224 µM for shikimate and ATP, respectively, and a global reaction rate of 13.4 µmol/min/mg; it is suggested that SaSK utilizes the Bi-Bi Ping Pong reaction mechanism. Furthermore, the physicochemical data indicated that SaSK is an unstable, hydrophilic, and acidic protein. Finally, structural information showed that SaSK presented folding that is typical of its homologous counterparts and contains the typical domains of this family of proteins. Amino acids that have been shown to be important for SaSK protein function are conserved. Therefore, this study provides fundamental information that may aid in the design of inhibitors that could be used to develop new antibacterial agents.
Subject(s)
Methicillin-Resistant Staphylococcus aureus/enzymology , Phosphotransferases (Alcohol Group Acceptor)/chemistry , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Adenosine Triphosphate/metabolism , Drug Design , Enzyme Stability , Kinetics , Models, Molecular , Molecular Dynamics Simulation , Phosphotransferases (Alcohol Group Acceptor)/genetics , Protein Binding , Protein Conformation , Protein Folding , Shikimic Acid/metabolism , Structural Homology, ProteinABSTRACT
Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.
