Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance
- Daina Zeng1,
- Dmitri Debabov2,
- Theresa L. Hartsell3,
- Raul J. Cano4,5,
- Stacy Adams6,
- Jessica A. Schuyler4,
- Ronald McMillan4 and
- John L. Pace4,7,8
- 1Agile Sciences, Raleigh, North Carolina 27606
- 2Emery Pharma Services, Emeryville, California 94608
- 3Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins School of Medicine and Nursing, Baltimore, Maryland 21287
- 4ATCC Center for Translational Microbiology, Union, New Jersey 07083
- 5Biological Sciences Department, California Polytechnic State University, San Luis Obispo, California 93407
- 6Center for Skin Biology, GlaxoSmithKline, Durham, North Carolina 27703
- 7STEM Program, Kean University, Union, New Jersey 07083
- 8Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, North Carolina 27707
- Correspondence: daina.zeng{at}gmail.com
Abstract
The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis. This is achieved primarily through binding to the d-alanyl-d-alanine terminus of the lipid II bacterial cell-wall precursor, preventing cross-linking of the peptidoglycan layer. Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillin-resistant Staphylococcus aureus and of susceptible Enterococcus spp. Newer lipoglycopeptide derivatives (telavancin, dalbavancin, and oritavancin) were designed in a targeted fashion to increase antibacterial activity, in some cases through secondary mechanisms of action. Resistance to the glycopeptides emerged in delayed fashion and occurs via a spectrum of chromosome- and plasmid-associated elements that lead to structural alteration of the bacterial cell-wall precursor substrates.
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