Dendrogram showing pulsed-field gel electrophoresis (PFGE) analysis and multilocus sequence typing (MLST) results for 8 <i>bla</i>_NDM-1-positive <i>E</i>. <i>cloacae</i> isolates.

<p>Dendrogram showing pulsed-field gel electrophoresis (PFGE) analysis and multilocus sequence typing (MLST) results for 8 <i>bla</i>_NDM-1-positive <i>E</i>. <i>cloacae</i> isolates.</p

Detection of resistance determinants in the 11 carbapenem-resistant <i>E</i>. <i>cloacae</i> isolates.

<p>Detection of resistance determinants in the 11 carbapenem-resistant <i>E</i>. <i>cloacae</i> isolates.</p

Characteristics of <i>bla</i>_NDM-1-positive <i>E</i>. <i>cloacae</i>.

<p>^<i>a</i> ST: Sequence type determined by multilocus sequence typing (MLST)</p><p>^<i>b</i> Resistance markers that are co-transferred with <i>bla</i>_NDM-1by conjugation are underlined. Minus signs indicate negative results.</p><p>Characteristics of <i>bla</i>_NDM-1-positive <i>E</i>. <i>cloacae</i>.</p

Detection of <i>bla</i>_NDM-1 carrying plasmids by S1 nuclease PFGE and Southern hybridization.

<p>Lanes M, marker (<i>Salmonella</i> H9812); Lane 1, ECL-2; Lane 2, ECL-4; Lane 3, ECL-37; Lane 4, ECL-62; Lane 5, ECL-27; Lane 6, ECL-ZMD10; Lane 7, ECL-ZMD12; Lane 8, ECL-36.</p

New Delhi Metallo-β-Lactamase 1(NDM-1), the Dominant Carbapenemase Detected in Carbapenem-Resistant <i>Enterobacter cloacae</i> from Henan Province, China

<div><p>The emergence of New Delhi metallo-β-lactamase 1 (NDM-1) has become established as a major public health threat and represents a new challenge in the treatment of infectious diseases. In this study, we report a high incidence and endemic spread of NDM-1-producing carbapenem-resistant <i>Enterobacter cloacae</i> isolates in Henan province, China. Eight (72.7%) out of eleven non-duplicated carbapenem-resistant <i>E</i>. <i>cloacae</i> isolates collected between June 2011 and May 2013 were identified as NDM-1 positive. The <i>bla</i>_NDM-1 gene surrounded by an entire IS<i>Aba</i>125 element and a bleomycin resistance gene <i>ble</i>_MBL in these isolates were carried by diverse conjugatable plasmids (IncA/C, IncN, IncHI2 and untypeable) ranging from ~55 to ~360 kb. Molecular epidemiology analysis revealed that three NDM-1-producing <i>E</i>. <i>cloacae</i> belonged to the same multilocus sequence type (ST), ST120, two of which were classified as extensively drug-resistant (XDR) isolates susceptible only to tigecycline and colistin. The two XDR ST120 <i>E</i>. <i>cloacae</i> isolates co-harbored <i>bla</i>_NDM-1, <i>armA</i> and <i>fosA3</i> genes and could transfer resistance to carbapenems, fosfomycin and aminoglycosides simultaneously via a conjugation experiment. Our study demonstrated NDM-1 was the most prevalent metallo-β-lactamase (MBL) among carbapenem-resistant <i>E</i>.<i>cloacae</i> isolates and identified a potential endemic clone of ST120 in Henan province. These findings highlight the need for enhanced efforts to monitor the further spread of NDM-1 and XDR ST120 <i>E</i>. <i>cloacae</i> in this region.</p></div

Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis

Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis

Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis

Discovery of [1,2,3]Triazolo[4,5‑<i>d</i>]pyrimidine Derivatives as Novel LSD1 Inhibitors

Lysine specific demethylase 1 (LSD1) plays a pivotal role in regulating the lysine methylation. The aberrant overexpression of LSD1 has been reported to be involved in the progression of certain human malignant tumors. Abrogation of LSD1 with RNAi or small molecule inhibitors may lead to the inhibition of cancer proliferation and migration. Herein, a series of [1,2,3]­triazolo­[4,5-<i>d</i>]­pyrimidine derivatives were synthesized and evaluated for their LSD1 inhibitory effects. The structure–activity relationship studies (SARs) were conducted by exploring three regions of this scaffold, leading to the discovery of compound <b>27</b> as potent LSD1 inhibitor (IC₅₀ = 0.564 μM). Compound <b>27</b> was identified as a reversible LSD1 inhibitor and showed certain selectivity to LSD1 over monoamine oxidase A/B (MAO-A/B). When MGC-803 cells were treated with compound <b>27</b>, the activity of LSD1 can be significantly inhibited, and the cell migration ability was also suppressed. Docking studies indicated that the hydrogen interaction between the nitrogen atom in the pyridine ring and Met332 could be responsible for the improved activity of 2-thiopyridine series. The [1,2,3]­triazolo­[4,5-<i>d</i>]­pyrimidine scaffold can be used as the template for designing new LSD1 inhibitors

Discovery of 5‑Cyano-6-phenylpyrimidin Derivatives Containing an Acylurea Moiety as Orally Bioavailable Reversal Agents against P‑Glycoprotein-Mediated Mutidrug Resistance

P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has become a major obstacle in successful cancer chemotherapy, which attracted much effort to develop clinically useful compounds to reverse MDR. Here, we designed and synthesized a novel series of derivatives with a 5-cyano-6-phenylpyrimidine scaffold and evaluated their potential reversal activities against MDR. Among these compounds, <b>55</b>, containing an acylurea appendage, showed the most potent activity in reversing paclitaxel resistance in SW620/AD300 cells. Further studies demonstrated <b>55</b> could increase accumulation of PTX, interrupt ABCB1-mediated Rh123 accumulation and efflux, stimulate ABCB1 ATPase activity, and especially have no effect on CYP3A4 activity, which avoid drug interaction caused toxicity. More importantly, <b>55</b> significantly enhanced the efficacy of PTX against the SW620/AD300 cell xenograft without obvious side effects for orally intake. Given all that, the pyrimidine-acylurea based ABCB1 inhibitor may be a promising lead in developing new efficacious ABCB1-dependent MDR modulator