Search

Background Epidemiology of fosfomycin susceptibility and the plasmid-mediated fosfomycinase genes of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates in Taiwan remain unclear. Methods 642 CRKP clinical isolates were collected from a nation-wide surveillance study (16 hospitals) in Taiwan in 2012–2013. Antimicrobial susceptibilities were determined. PFGE and MLST determined the clonal relatedness. Carbapenemases and fosfomycinases genes were detected by PCR, and their flanking regions were determined by PCR and sequencing. Synergistic activity of meropenem with fosfomycin was examined by the checkerboard method. Results In total, 36.4% (234/642) of CRKP isolates in Taiwan were resistant to fosfomycin. Among 234 fosfomycin-resistant CRKP isolates, PFGE analysis revealed 81 pulsotypes. Pulsotype XXIII (n = 63) was predominant and belonged to ST11. 71 had carbapnemases (65 bla KPC-2 -positive, 1 bla VIM-1 -positive and 5 bla IMP-8 -positive) and 62 had fosfomycinases (35 fosA3 -positive and 27 foskp96 -positive). Only 18.5% (5/27) of foskp96 -positive isolates carried foskp96 and bla KPC-2 , while 71.4% (25/35) of fosA3 -positive isolates contained fosA3 and bla KPC-2 . There were five types of flanking sequences for fosA3 , and 85.7% (30/35) of fosA3 genes were flanked by IS 26 , suggesting possible horizontal gene transfer. Synergistic effect of fosfomycin and meropenem was observed in all 25 randomly selected pulsotype XXIII strains (100%; 25/25), even those containing fosfomycinase (48%, 12/25) or carbapnemase (96%, 24/25). Conclusions A clone (pulsotype XXIII, ST11) has been found to be prevailing among fosfomycin-resistant CRKP in Taiwan. According to the in vitro data, the combination of fosfomycin and meropenem is a potentially alternative choice.

Nitric oxide (NO) is an important cellular signaling molecule that modulates various physiological activities. Angiogenesis-promoting activities of NO-donor drugs have been explored in both experimental and clinical studies. In this study, a structurally well characterized and water-soluble neutral {Fe(NO)2}(9) DNIC [(S(CH2)2OH)(S(CH2)2NH3)Fe(NO)2] (DNIC 2) was synthesized to serve as a NO-donor species. The antitumor activity of DNIC 2 was determined by MTT assay, confocal imaging, and Annexin-V/PI staining. The IC50 values of DNIC 2 were 18.8, 42.9, and 38.6 μM for PC-3, SKBR-3, and CRL5866 tumor cells, respectively. Moreover, DNIC 2 promoted apoptotic cell death via activation of apoptosis-associated proteins and inhibition of survival associated proteins. In particular, DNIC 2 treatment suppressed PC-3 tumor growth by 2.34- and 19.3-fold at 7 and 21 days, in comparison with the control group. These results indicate that water-soluble DNIC 2 may serve as a promising drug for cancer therapy.

Acute leukemia is one of the commonly diagnosed neoplasms and causes human death. However, the treatment for acute leukemia is not yet satisfactory. Studies have shown that mushroom-derived polysaccharides display low toxicity and have been used clinically for cancer therapy. Therefore, we set out to evaluate the anti-cancerous efficacy of a water-soluble polysaccharide extract from Inonotus taiwanensis (WSPIS) on human acute monocytic leukemia THP-1 and U937 cell lines in vitro. Under our experimental conditions, WSPIS elicited dose-dependent growth retardation and induced apoptotic cell death. Further analysis showed that WSPIS-induced apoptosis was associated with a mitochondrial apoptotic pathway, such as the disruption of mitochondrial membrane potential (MMP), followed by the activation of caspase-9, caspase-3, and PARP (poly(ADP-ribose) polymerase) cleavage. However, a broad caspase inhibitor, Z-VAD.fmk, could not prevent WSPIS-induced apoptosis. These data imply that mechanism(s) other than caspase might be involved. Thus, the involvement of endonuclease G (endoG), a mediator arbitrating caspase-independent oligonucleosomal DNA fragmentation, was examined. Western blotting demonstrated that WSPIS could elicit nuclear translocation of endoG. MMP disruption after WSPIS treatment was accompanied by intracellular reactive oxygen species (ROS) generation. However, pretreatment with N-acetyl-l-cysteine (NAC) could not attenuate WSPIS-induced apoptosis. In addition, our data also show that WSPIS could inhibit autophagy. Activation of autophagy by rapamycin decreased WSPIS-induced apoptosis and cell death. Taken together, our findings suggest that cell cycle arrest, endonuclease G-mediated apoptosis, and autophagy inhibition contribute to the anti-cancerous effect of WSPIS on human acute monocytic leukemia cells.

Three new imido tungsten derivatives containing bi-dentate pyrrole-amine, pyrrole-imine or ketiminate precursor were synthesized and characterized. Reacting W( NtBu)2(NHtBu)2 with two equiv of C4H3NH(2-CH2NHtBu) and C4H3NH(2-CH NCH2Py) in diethyl ether and toluene generates [W( NtBu)2{C4H3N(2-CH2NHtBu)}2] (1) and [W( NtBu)2{C4H3N(2-CH NCH2Py)}2] (2) in good yield. Similarly, while subjecting two equiv of (ArNCMeCHCMeOH) (Ar = 2-MeOC6H4) with W( NtBu)2(NHtBu)2 in diethyl ether, affords [W( NtBu)2{OCMeCHCMeNAr}2] (3) in high yield. Single crystal X-ray structure reveals that in all three complexes the 6-coordinate W atoms belong to a distorted octahedral environment.

The reactions of Zn-alkyls with bidentate as well as symmetrical and asymmetrical tridentate pyrrolyl ligands, have been carried out and characterized. Reacting ZnR2 with 1 equiv of C4H3NH(2-CH2NHtBu) in diethyl ether yields [Zn{C4H3N(2-CH2NHtBu)}R] (1, R = Me; 2, R = Et) in high yield. Similarly, the reactions of 2 equiv of C4H3NH(2-CH2NHtBu) and ZnR2 (R = Me, Et) in toluene both produce [Zn{C4H3N(2-CH2NHtBu)}2] (3). Furthermore, while subjecting 2 equiv of C4H2NH(2-CH2NHtBu)(5-CH2NMe2) with ZnMe2 in diethyl ether, affords [Zn{C4H2N(2-CH2NHtBu)(5-CH2NMe2)}2] (4) and additionally, reacting C4H2NH(2,5-CH2NHtBu)2 with ZnMe2 generates [Zn{C4H2N(2,5-CH2NHtBu)2}2] (5) in satisfactory yield. All the aforementioned compounds were characterized by 1H and 13C NMR spectrometry and the molecular structures were determined by single crystal X-ray diffractometry. Compounds 1, 3, 4 and 5 are moderate catalysts for the ring-opening polymerization of e-caprolactone in toluene.