Abstract
Humanity is facing an increasing health threat caused by a variety of multidrug resistant bacteria. Within this scenario, Staphylococcus aureus, in particular methicillin resistant S. aureus (MRSA), is responsible for a number of hospital-acquired bacterial infections. The emergence of microbial antibiotic resistance urgently requires the identification of new and innovative strategies to treat antibiotic resistant microorganisms. In this context, structure and function analysis of potential drug targets in metabolic pathways vital for bacteria endurance, such as the vitamin K2 synthesis pathway, becomes interesting. We have solved and refined the crystal structure of the S. aureus DHNA thioesterase (SaDHNA), a key enzyme in the vitamin K2 pathway. The crystallographic structure in combination with small angle X-ray solution scattering data revealed a functional tetramer of SaDHNA. Complementary activity assays of SaDHNA indicated a preference for hydrolysing long acyl chains. Site-directed mutagenesis of SaDHNA confirmed the functional importance of Asp16 and Glu31 for thioesterase activity and substrate binding at the putative active site, respectively. Docking studies were performed and rational designed peptides were synthesized and tested for SaDHNA inhibition activity. The high-resolution structure of SaDHNA and complementary information about substrate binding will support future drug discovery and design investigations to inhibit the vitamin K2 synthesis pathway.
Highlights
Humanity is facing an increasing health threat caused by a variety of multidrug resistant bacteria
The widespread use of methicillin has led to the emergence of Methicillin resistant S. aureus (MRSA) by acquisition of a non-active gene encoding a PBP2a which has a lower affinity for β-lactam a ntibiotics[5]
The respective affinity constants for Pep 1 and Pep 2 were 72.7 ± 2.9 M−1 and 3.4 ± 0.9 M−1, indicating that Pep-1 has a 21-fold higher binding affinity to S. aureus DHNA thioesterase (SaDHNA) than Pep[2]. These results strongly indicate Pep-1 as a suitable candidate to be considered as a lead compound for further drug development investigations, to identify compounds that can directly interact with and inhibit SaDHNA, an essential enzyme of the menaquinone pathway (Fig. S1)
Summary
Humanity is facing an increasing health threat caused by a variety of multidrug resistant bacteria. Within this scenario, Staphylococcus aureus, in particular methicillin resistant S. aureus (MRSA), is responsible for a number of hospital-acquired bacterial infections. The emergence of microbial antibiotic resistance urgently requires the identification of new and innovative strategies to treat antibiotic resistant microorganisms In this context, structure and function analysis of potential drug targets in metabolic pathways vital for bacteria endurance, such as the vitamin K2 synthesis pathway, becomes interesting. The most frequent SCV phenotypes are mutations in genes involved in the biosynthesis of components required for the electron transport chain, reducing the emergence of new therapies for MRSA
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