4 research outputs found
Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis
Recently,
we reported a novel role for KMO in the pathogenesis
of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase
(KMO) have previously been described as potential treatments for neurodegenerative
conditions and particularly for Huntingtonâs disease. However,
the inhibitors reported to date have insufficient aqueous solubility
relative to their cellular potency to be compatible with the intravenous
(iv) dosing route required in AP. We have identified and optimized
a novel series of high affinity KMO inhibitors with favorable physicochemical
properties. The leading example is exquisitely selective, has low
clearance in two species, prevents lung and kidney damage in a rat
model of acute pancreatitis, and is progressing into preclinical development
Novel HldEâK Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence
We report here the optimization of an HldE kinase inhibitor
to
low nanomolar potency, which resulted in the identification of the
first reported compounds active on selected <i>E. coli</i> strains. One of the most interesting candidates, compound <b>86</b>, was shown to inhibit specifically bacterial LPS heptosylation
on efflux pump deleted <i>E. coli</i> strains. This compound
did not interfere with <i>E. coli</i> bacterial growth (MIC
> 32 Îźg/mL) but sensitized this pathogen to hydrophobic antibiotics
like macrolides normally inactive on Gram-negative bacteria. In addition, <b>86</b> could sensitize <i>E. coli</i> to serum complement
killing. These results demonstrate that HldE kinase is a suitable
target for drug discovery. They also pave the way toward novel possibilities
of treating or preventing bloodstream infections caused by pathogenic
Gram negative bacteria by inhibiting specific virulence factors
StructuralâFunctional Studies of <i>Burkholderia cenocepacia</i> dâGlycero-βâdâmanno-heptose 7âPhosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties
As an essential constituent of the outer membrane of
Gram-negative bacteria, lipopolysaccharide contributes significantly
to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic
pathway therefore serves as a promising therapeutic target for antivirulence
drugs and antibiotic adjuvants. Here we report the structuralâfunctional
studies of d-glycero-β-d-manno-heptose 7-phosphate
kinase (HldA), an absolutely conserved enzyme in this pathway, from <i>Burkholderia cenocepacia</i>. HldA is structurally similar to
members of the PfkB carbohydrate kinase family and appears to catalyze
heptose phosphorylation via an in-line mechanism mediated mainly by
a conserved aspartate, Asp270. Moreover, we report the structures
of HldA in complex with two potent inhibitors in which both inhibitors
adopt a folded conformation and occupy the nucleotide-binding sites.
Together, these results provide important insight into the mechanism
of HldA-catalyzed heptose phosphorylation and necessary information
for further development of HldA inhibitors
From Triclosan toward the Clinic: Discovery of Nonbiocidal, Potent FabI Inhibitors for the Treatment of Resistant Bacteria
In this paper, we present some elements of our optimization
program
to decouple triclosanâs specific FabI effect from its nonspecific
cytotoxic component. The implementation of this strategy delivered
highly specific, potent, and nonbiocidal new FabI inhibitors. We also
disclose some preclinical data of one of their representatives, <b>83</b>, a novel antibacterial compound active against resistant
staphylococci and some clinically relevant Gram negative bacteria
that is currently undergoing clinical trials