Continuous flow synthesis and antimicrobial evaluation of NHC* silver carboxylate derivatives of SBC3 in vitro and in vivo

N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC–silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa, and K. pneumoniae; further studies also confirmed the ability to inhibit biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA) and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*).European Commission - European Regional Development FundScience Foundation IrelandSchool of Chemistry & the College of Science of University College Dubli

Continuous flow synthesis and antimicrobial evaluation of NHC* silver carboxylate derivatives of SBC3 in vitro and in vivo

N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC–silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa, and K. pneumoniae; further studies also confirmed the ability to inhibit biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA) and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC

FokI vitamin D receptor polymorphism as a protective factor in intrahepatic cholestasis of pregnancy

Objectives: Intrahepatic cholestasis in pregnancy (ICP) is a pregnancy-specific liver disorder. Its etiology is not fully understood. Increasing evidence indicates the important role of vitamin D and the vitamin D receptor (VDR) in this disorder. The presence of polymorphic variants in the VDR gene could influence its activity and susceptibility to ICP development. The goal of the study was to investigate the role of four genetic polymorphisms of the VDR gene — Fok (rs731236), Bsm (rs1544410), Apa (rs7975232), and Taq (rs731236) — in the etiology of ICP in Polish women. Material and methods: Ninety-eight women with confirmed ICP and 215 healthy pregnant women as a control group were recruited to the study. We examined four SNPs of the VDR gene: BsmI (rs7975232), TaqI (rs1544410), ApaI (rs228570), FokI (rs731236). Genotyping was performed using the PCR/RFLP method. Results: We observed higher frequency (borderline significant) of the Ff-ff genotypes containing at least one mutated allele of the VDR FokI polymorphism in the control group compared to the ICP group (p = 0.045, OR = 1.71, 95% CI 1.01–2.88). The frequency of the mutated f allele was slightly higher in controls (49.1%) than in the ICP group (43.4%) (OR = 1.26, 95% CI 0.90–1.77), but the difference was not statistically significant (p = 0.196). Conclusions: Our results showed that the maternal VDR FokI polymorphism could play a protective role in ICP development and probably modulate the risk of ICP occurrence in pregnant women in the Polish population. In the future, to confirm these observations, research in larger, ethnically stratified and clinically analyzed groups is necessary

Potent antimicrobial effect induced by disruption of chloride homeostasis

Artificial transmembrane ion transporters have proposed applicability to medicinal chemistry, where perturbation of normal cellular homeostasis has already been shown to induce apoptosis in mammalian cells; however, this effect has not been observed in bacteria. In this study, we report the synthesis and structural characterization of a new class of fluorescent anionophores that effectively kill Gram-positive bacteria by disrupting normal Na+ and Cl- concentrations.The so-called "squindoles"take advantage of both NH and CH hydrogen-bonding interactions to bind chloride with high affinity and act as efficient anion transporters, as measured by lipid vesicle transport assays. The most active transporter shows potent inhibitory activity against Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA). Cell-based as-says and label-free quantitative proteomic profiling suggest that the mode of action is directly related to the anion-transport ability, whereby an influx of chloride into bacterial cells significantly affects their proteome and induces several known stress responses