Computational study of glycopeptide antibiotics interactions with Staphylococcus aureus peptidoglycan.


Staphylococcus aureus is generally known for its ability to acquire resistance to any antibiotic. Methicillin-resistant S. aureus is one of the leading etiological agents responsible for the hospital- and community-acquired infections. Due to the rise of multidrug resistant bacteria, there is a great need for continuous discovery and development of new antibiotics to overcome the inevitable emergence of antibiotic resistance in pathogens. Numerous classes of antibiotics, including glycopeptide antibiotics, target bacterial cell wall biosynthesis, where the cell wall plays an essential role in maintaining the structural integrity and morphology of bacteria. The major component of the cell wall is peptidoglycan (PG), a unique feature found in all bacteria. Inhibition of PG biosynthesis during cell growth results in bacterial cell lysis. This dissertation examines the glycopeptide antibiotics interactions with PG by molecular dynamics simulations to provide insight into modifying existing therapeutics or developing novel pharmacological therapeutics. Steered molecular dynamics simulations and umbrella sampling were also applied, when necessary, to characterize the thermodynamic properties and the dynamics of select glycopeptide-PG complexes. Our simulations provide insights into the role of amino acid residues, which are not directly involved in the dipeptide binding of glycopeptides, in improving the binding of the glycopeptides to PG. We also reveal computational evidence of a secondary-binding site contributing to the enhancement in the binding of oritavancin to PG compared to other glycopeptide antibiotics lacking the additional binding interactions.



Staphylococcus aureus. Glycopeptide. Peptidoglycan. Oritavancin.