Endothelial C-type natriuretic peptide maintains vascular homeostasis

PMCID: PMC4151218Wellcome Trust (084449/Z/07/Z and 078496/Z/05/Z

Small Molecule Suppression of Carbapenem Resistance in NDM-1 Producing <i>Klebsiella pneumoniae</i>

The already considerable global public health threat of multidrug-resistant Gram-negative bacteria has become even more of a concern following the emergence of New Delhi metallo-β-lactamase (NDM-1) producing strains of <i>Klebsiella pneumoniae</i> and other Gram-negative bacteria. As an alternative approach to the traditional development of new bactericidal entities, we have identified a 2-aminoimidazole-derived small molecule that acts as an antibiotic adjuvant and is able to suppress resistance of a NDM-1 producing strain of <i>K. pneumoniae</i> to imipenem and meropenem, in addition to suppressing resistance of other β-lactam nonsusceptible <i>K. pneumoniae</i> strains. The small molecule is able to lower carbapenem minimum inhibitory concentrations by up to 16-fold, while exhibiting little bactericidal activity itself

Small Molecule Downregulation of PmrAB Reverses Lipid A Modification and Breaks Colistin Resistance

Infections caused by multi-drug resistant bacteria, particularly Gram-negative bacteria, are an ever-increasing problem. While the development of new antibiotics remains one option in the fight against bacteria that have become resistant to currently available antibiotics, an attractive alternative is the development of adjuvant therapeutics that restore the efficacy of existing antibiotics. We report a small molecule adjuvant that suppresses colistin resistance in multidrug resistant <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i> by interfering with the expression of a two-component system. The compound downregulates the <i>pmrCAB</i> operon and reverses phosphoethanolamine modification of lipid A responsible for colistin resistance. Furthermore, colistin-susceptible and colistin-resistant bacteria do not evolve resistance to combination treatment. This represents the first definitive example of a compound that breaks antibiotic resistance by directly modulating two-component system activity

Homopolymeric pyrrolidine-amide oligonucleotide mimics: Fmoc-synthesis and DNA/RNA binding properties

By chemically modifying or replacing the backbone of oligonucleotides it is possible to modulate the DNA and RNA recognition properties and fine-tune the physiochemical properties of oligomers. This is important because it challenges our understanding of natural nucleic acid structural and recognition properties and can lead to nucleic acid mimics with a wide range of applications in nucleic acid targeting, analysis or diagnostics. In this paper we describe the solid phase synthesis of pyrrolidine-amide oligonucleotide mimics (POMs) using Fmoc-peptide chemistry. This required the synthesis of adeninyl, cytosinyl, thyminyl and guaninyl pyrrolidine monomers, with Fmoc- and standard acyl-protecting groups on the exocyclic amino groups and nucleobases respectively. These monomers were used to synthesise several thyminyl and adeninyl POM pentamers, with modest coupling efficiency. The pentamers were purified by RP-HPLC, characterised by mass spectrometry and their DNA and RNA binding properties were investigated using UV thermal denaturation/renaturation experiments. This revealed that all the pentamers exhibit strong affinity for complementary nucleic acids. The further evaluation of longer mixed-sequence POMs is described in a second accompanying paper (R. J. Worthington et al., Org. Biomol. Chem., 2006, DOI: 10.1039/b613386j)