Molecular dynamics simulations of the secondary-binding site in disaccharide-modified glycopeptide antibiotics

Journal Article · Sat Apr 30 00:00:00 UTC 2022 · Scientific Reports

DOI: https://doi.org/10.1038/s41598-022-10735-6 · OSTI ID:1904346

Olademehin, Olatunde P. ^[1]; Shuford, Kevin L. ^[2]; Kim, Sung J. ^[3]

---

1. Baylor Univ., Waco, TX (United States); OSTI
2. Baylor Univ., Waco, TX (United States)
3. Howard Univ., Washington, DC (United States)

Oritavancin is a semisynthetic glycopeptide antibiotic used to treat severe infections by multidrug-resistant Gram-positive pathogens. Oritavancin is known to be a thousand times more potent than vancomycin against Gram-positive bacteria due to the additional interactions with bacterial peptidoglycan (PG) facilitated by a secondary-binding site. The presence of this secondary-binding site is evident in desleucyl-oritavancin, an Edman degradation product of oritavancin, still retaining its potency against Gram-positive bacteria, whereas desleucyl-vancomycin is devoid of any antimicrobial activities. Herein, using explicit solvent molecular dynamics (MD) simulations, steered MD simulations, and umbrella sampling, we show evidence of a secondary-binding site mediated by the disaccharide-modified hydrophobic sidechain of oritavancin interactions with the pentaglycyl-bridge segment of the PG. The interactions were characterized through comparison to the interaction of PG with chloroeremomycin, vancomycin, and the desleucyl analogs of the glycopeptides. Our results show that the enhanced binding of oritavancin to PG over the binding of the other complexes studied is due to an increase in the hydrophobic effect, electrostatic and van der Waals interactions, and not the average number of hydrogen bonds. Our ranking of the binding interactions of the biomolecular complexes directly correlates with the order based on their experimental minimum inhibitory concentrations. The results of our simulations provide insight into the modification of glycopeptides to increase their antimicrobial activities or the design of novel antibiotics against pathogenic Gram-positive bacteria.

• Research Organization: Baylor Univ., Waco, TX (United States)
• Sponsoring Organization: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division (CSGB)
• Grant/Contract Number: SC0019327
• OSTI ID: 1904346
• Journal Information: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 12; ISSN 2045-2322
• Publisher: Nature Publishing GroupCopyright Statement
• Country of Publication: United States
• Language: English