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. 2018 May 11;4(5):715-735.
doi: 10.1021/acsinfecdis.7b00258. Epub 2018 Feb 19.

Developments in Glycopeptide Antibiotics

Mark A T Blaskovich  1   2 , Karl A Hansford  1   2 , Mark S Butler  1   2 , ZhiGuang Jia  1   2 , Alan E Mark  1   2 , Matthew A Cooper  1   2
Affiliations

Developments in Glycopeptide Antibiotics

Mark A T Blaskovich et al. ACS Infect Dis. .

Abstract

Glycopeptide antibiotics (GPAs) are a key weapon in the fight against drug resistant bacteria, with vancomycin still a mainstream therapy against serious Gram-positive infections more than 50 years after it was first introduced. New, more potent semisynthetic derivatives that have entered the clinic, such as dalbavancin and oritavancin, have superior pharmacokinetic and target engagement profiles that enable successful treatment of vancomycin-resistant infections. In the face of resistance development, with multidrug resistant (MDR) S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) together causing 20-fold more infections than all MDR Gram-negative infections combined, further improvements are desirable to ensure the Gram-positive armamentarium is adequately maintained for future generations. A range of modified glycopeptides has been generated in the past decade via total syntheses, semisynthetic modifications of natural products, or biological engineering. Several of these have undergone extensive characterization with demonstrated in vivo efficacy, good PK/PD profiles, and no reported preclinical toxicity; some may be suitable for formal preclinical development. The natural product monobactam, cephalosporin, and β-lactam antibiotics all spawned multiple generations of commercially and clinically successful semisynthetic derivatives. Similarly, next-generation glycopeptides are now technically well positioned to advance to the clinic, if sufficient funding and market support returns to antibiotic development.

Keywords: antibiotics; antimicrobial resistance; glycopeptides; vancomycin.

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Conflict of interest statement

The authors declare the following competing financial interest(s): M.A.C. and M.A.T.B. are inventors on WO 2015/117196 A, describing new glycopeptide derivatives discussed in this Review and subject to commercialization activities.

Figures

Figure 1
Figure 1
Comparison of annual drug-resistant infection (DRI) cases and deaths in the USA due to Gram-positive (MRSA or MDR S. pneumoniae) or Gram-negative (MDR P. aeruginosa, MDR Acinetobacter, and extended-spectrum β-lactamase CRE) drug-resistant bacteria.
Figure 2
Figure 2
(A) Molecular dynamics simulation of vancomycin 1 interacting with membrane-bound Lipid II, demonstrating vancomycin dimerization. (B) Hydrogen bond interactions between vancomycin 1 backbone and d-Ala-d-Ala component of Lipid II.
Figure 3
Figure 3
Timeline of discovery for the clinically used glycopeptide antibiotics vancomycin 1, ristocetin 2, teicoplanin 3, telavancin 4, dalbavancin 5, and oritavancin 6b.
Figure 4
Figure 4
Structures of clinically approved semisynthetic glycopeptides telavancin 4, dalbavancin 5, and oritavancin 6b (derived from chloroeremomycin 6a). Differences from vancomycin are highlighted in blue for 4 and 6 and from teicoplanin, in red for 5.
Figure 5
Figure 5
Potential sites for modification of vancomycin 1.
Figure 6
Figure 6
Membrane-targeting strategies to increase vancomycin potency.
Figure 7
Figure 7
Additional membrane-targeting strategies to increase vancomycin potency.
Figure 8
Figure 8
Backbone modifications to overcome vancomycin VRE/VRSA resistance.
Figure 9
Figure 9
Aryl ring modifications.
Figure 10
Figure 10
Hydroxy and N-terminal modifications.
Figure 11
Figure 11
Glycopeptide dimers.
Figure 12
Figure 12
Hybrid antibiotics.
Figure 13
Figure 13
Glycopeptide conjugates.
Figure 14
Figure 14
New glycopeptide scaffolds (removed biaryl linkages highlighted in yellow).
See this image and copyright information in PMC

References

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