Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae.

Article Details

Citation

Copy to clipboard

Lomovskaya O, Sun D, Rubio-Aparicio D, Nelson K, Tsivkovski R, Griffith DC, Dudley MN

Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae.

Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: AAC.01443-17. doi: 10.1128/AAC.01443-17. Print 2017 Nov.

PubMed ID

28848018 [ View in PubMed

]

Abstract

Vaborbactam (formerly RPX7009) is a new beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of beta-lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with beta-lactamases cloned from various classes and a panel of Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent inhibitor of class A carbapenemases, such as KPC, as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to the potencies of vaborbactam in combination with other antibiotics against strains producing the KPC beta-lactamase. Consistent with broad-spectrum beta-lactamase inhibition, vaborbactam reduced the meropenem MICs for engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of extended-spectrum beta-lactamase production, class C beta-lactamase production, and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC had a minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency showed that vaborbactam at 8 mug/ml results in meropenem MICs of

DrugBank Data that Cites this Article

Drugs

Vaborbactam

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Vaborbactam	Beta-lactamase	Protein	Enterobacter cloacae	Yes	Inhibitor	Details
Vaborbactam	Beta-lactamase	Protein	Klebsiella pneumoniae	Yes	Inhibitor	Details
Vaborbactam	Beta-lactamase (blaSHV)	Protein	Escherichia coli	Yes	Inhibitor	Details
Vaborbactam	Beta-lactamase (KPC-2)	Protein	Klebsiella pneumoniae	Yes	Inhibitor	Details
Vaborbactam	Beta-lactamase (MIR-1)	Protein	Klebsiella pneumoniae	Yes	Inhibitor	Details
Vaborbactam	Beta-lactamase CTX-M (Protein Group)	Protein group	Escherichia coli	Yes	Inhibitor	Details
Vaborbactam	Beta-lactamase SHV-1	Protein	Klebsiella pneumoniae	Yes	Inhibitor	Details
Vaborbactam	Beta-lactamase TEM	Protein	Escherichia coli	Yes	Inhibitor	Details
Vaborbactam	Carbapenem-hydrolyzing beta-lactamase KPC	Protein	Klebsiella pneumoniae	Yes	Inhibitor	Details