Novel pentadecenyl tetrazole enhances susceptibility of methicillin-resistant Staphylococcus aureus biofilms to gentamicin.

One method that bacteria employ to reduce their susceptibility to antibiotics is the formation of biofilms. We developed a robust 6-well plate biofilm assay to evaluate early-stage discovery compounds against methicillin-resistant Staphylococcus aureus (MRSA). Tissue culture-treated 6-well plates were selected for this assay because they facilitate the adherence of MRSA and enable accurate determination of the number of CFU in each well. The MRSA biofilms formed in this assay exhibit increased tolerances to clinically used antibiotics. Using this biofilm assay, we identified a novel potentiator of gentamicin against MRSA biofilms. The combination of gentamicin and pentadecenyl tetrazole is superior to clinically used MRSA antibiotics against these MRSA biofilms. This novel combination also exhibits synergistic effects on MRSA planktonic cells. This plant-derived compound reveals promise for its effectiveness and warrants further lead optimization as an antibiotic and aminoglycoside potentiator.

Antibiotic indole sesquiterpene alkaloid from Greenwayodendron suaveolens with a new natural product framework.

High-throughput natural products chemistry methods have led to the isolation of three new (1-3) and two known indole sesquiterpene alkaloids (4, 5) from Greenwayodendron suaveolens. Their structures were determined using CapNMR and MS. Pentacyclindole (1) was determined to possess a new natural product framework. Pentacyclindole (1) and polyalthenol (4) showed activity against clinical isolates of Staphylococcus aureus with polyalthenol (4) demonstrating a MIC(90) of 4 microg/mL.

Dammarane-type triterpene glycosides from Oncoba manii active against methicillin-resistant Staphylococcus aureus.

Drug-resistant bacteria are becoming more prevalent both in the community and in hospitals. In a search for new antibiotic leads, we used a high-throughput natural products chemistry approach to isolate one new (1) and two known (2, 3) dammarane-type triterpenes with mass-limited material from the African plant Oncoba manii. The new compound was determined by spectroscopic methods to be 1beta,2alpha,3beta,20(R)-tetrahydroxydammar-24-ene 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranoside. Compounds 1 and 2 inhibited the growth of methicillin-resistant Staphylococcus aureus (MRSA).

Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy.

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the alpha-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT(c) intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.