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Developments in Glycopeptide Antibiotics
#MMPMID29363950
Blaskovich MAT
; Hansford KA
; Butler MS
; Jia Z
; Mark AE
; Cooper MA
ACS Infect Dis
2018[May]; 4
(5
): 715-735
PMID29363950
show ga
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 ?-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.
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