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Groton, CT, United States

Tomaras A.P.,Antibacterials Research Unit | Crandon J.L.,Center for Anti Infective Research and Development | McPherson C.J.,Antibacterials Research Unit | Nicolau D.P.,Center for Anti Infective Research and Development
Antimicrobial Agents and Chemotherapy | Year: 2015

Preliminary enthusiasm over the encouraging spectrum and in vitro activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivo efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosa and provide evidence that efflux inhibition may circumvent this in vivo-relevant resistance liability. Copyright © 2015, American Society for Microbiology. All Rights Reserved. Source

Brown M.F.,Worldwide Medicinal Chemistry | Mitton-Fry M.J.,Worldwide Medicinal Chemistry | Arcari J.T.,Worldwide Medicinal Chemistry | Barham R.,Worldwide Medicinal Chemistry | And 28 more authors.
Journal of Medicinal Chemistry | Year: 2013

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1. © 2013 American Chemical Society. Source

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