11 research outputs found
Isolation of Human Lineage, Fluoroquinolone-Resistant and Extended-beta-Lactamase-Producing Escherichia coli Isolates from Companion Animals in Japan
An increase in human and veterinary fluoroquinolone-resistant Escherichia coli is a global concern. In this study, we isolated fluoroquinolone-resistant E. coli isolates from companion animals and characterized them using molecular epidemiological analysis, multiplex polymerase chain reaction to detect E. coli ST131 and CTX-M type extended-spectrum beta-lactamases (ESBL), and multi-locus sequence typing analysis. Using plain-CHROMagar ECC, 101 E. coli isolates were isolated from 34 rectal swabs of dogs and cats. The prevalence of resistance to fluoroquinolone and cefotaxime was 27.7% and 24.8%, respectively. The prevalence of fluoroquinolone-resistant isolates (89.3%) was higher when CHROMagar ECC with CHROMagar ESBL supplement was used for E. coli isolation. The prevalence of cefotaxime resistance was also higher (76.1%) when 1 mg/L of ciprofloxacin-containing CHROMagar ECC was used for isolation. The cefotaxime-resistant isolates possessed CTX-M type beta-lactamase genes (CTX-M-14, CTX-M-15, or CTX-M-27). Seventy-five percent of fluoroquinolone-resistant isolates were sequence types ST131, ST10, ST1193, ST38, or ST648, which are associated with extensive spread in human clinical settings. In addition, we isolated three common fluoroquinolone-resistant E. coli lineages (ST131 clade C1-M-27, C1-nM27 and ST2380) from dogs and their respective owners. These observations suggest that companion animals can harbor fluoroquinolone-resistant and/or ESBL-producing E. coli, in their rectums, and that transmission of these isolates to their owners can occur
Diaminopyridine-Based Potent and Selective Mps1 Kinase Inhibitors Binding to an Unusual Flipped-Peptide Conformation
Monopolar spindle 1 (Mps1) is an attractive cancer drug
target
due to the important role that it plays in centrosome duplication,
the spindle assembly checkpoint, and the maintenance of chromosomal
stability. A design based on JNK inhibitors with an aminopyridine
scaffold and subsequent modifications identified diaminopyridine <b>9</b> with an IC<sub>50</sub> of 37 nM. The X-ray structure of <b>9</b> revealed that the Cys604 carbonyl group of the hinge region
flips to form a hydrogen bond with the aniline NH group in <b>9</b>. Further optimization of <b>9</b> led to <b>12</b> with
improved cellular activity, suitable pharmacokinetic profiles, and
good in vivo efficacy in the mouse A549 xenograft model. Moreover, <b>12</b> displayed excellent selectivity over 95 kinases, indicating
the contribution of its unusual flipped-peptide conformation to its
selectivity