Examples of melting curves for each target region

<p>. For some target regions not all melting curves were represented among the isolates analysed in this study, therefore not all theoretically possible curves are depicted in the figure. <b>A</b>) Target region <i>infB</i>729, showing two (12, 13) of two predicted melting curves. <b>B</b>) Target region <i>mdh</i>1197, showing two (9, 10) of three predicted melting curves. <b>C</b>) Target region <i>pho</i>E2013, showing four (18, 19, 20, 21) of four predicted melting curves. <b>D</b>) Target region <i>rpoB</i>2227, showing six (41, 42 43, 44, 45, 46) of seven predicted melting curves. <b>E</b>) Target region <i>tonB</i>2693, showing three (39, 40, 41) of seven predicted melting curves. <b>F</b>) Target region <i>tonB</i>2886, showing three (54, 55, 56) of eight predicted melting curves.</p

Power of Minim typing to identify and discriminate <i>K. pneumoniae</i> STs of particular significance.

<p>*SLV = single locus variant, DLV = double locus variant, TLV = triple locus variant, QLV = quadruple locus variant.</p

Discriminatory power from different combinations of markers, calculated against all STs (863 STs, <i>D</i> = 1).

<p>Discriminatory power from different combinations of markers, calculated against all STs (863 STs, <i>D</i> = 1).</p

Indices of association for combinations of MLST alleles with and without <i>tonB</i>, and measurements of diversity conferred by individual loci indicate that <i>tonB</i> is highly diverse and likely subjected to horizontal gene transfer.

<p>Indices of association for combinations of MLST alleles with and without <i>tonB</i>, and measurements of diversity conferred by individual loci indicate that <i>tonB</i> is highly diverse and likely subjected to horizontal gene transfer.</p

Biotin Analogues with Antibacterial Activity Are Potent Inhibitors of Biotin Protein Ligase

There is a desperate need to develop new antibiotic agents to combat the rise of drug-resistant bacteria, such as clinically important <i>Staphylococcus aureus</i>. The essential multifunctional enzyme, biotin protein ligase (BPL), is one potential drug target for new antibiotics. We report the synthesis and characterization of a series of biotin analogues with activity against BPLs from <i>S. aureus</i>, <i>Escherichia coli</i>, and <i>Homo sapiens</i>. Two potent inhibitors with <i>K</i>_i < 100 nM were identified with antibacterial activity against a panel of clinical isolates of <i>S. aureus</i> (MIC 2–16 μg/mL). Compounds with high ligand efficiency and >20-fold selectivity between the isozymes were identified and characterized. The antibacterial mode of action was shown to be via inhibition of BPL. The bimolecular interactions between the BPL and the inhibitors were defined by surface plasmon resonance studies and X-ray crystallography. These findings pave the way for second-generation inhibitors and antibiotics with greater potency and selectivity

Structure activity relationship between NCL812, NCL195 and NCL219.

<p>Installation of a 4-<i>tert</i>-butyl and a C-methyl imine moiety provided NCL219 with considerably enhanced hydrolytic stability while retaining the excellent antimicrobial activity of NCL812, while guanidine to 2,4,6-triaminopyrimindine bioisosteric modification yielded NCL195, which allowed potency and drug-like character enhancement.</p

Antimicrobial activity of NCL195 against Gram-negative bacteria alone and in combination with EDTA or polymyxin B.

<p>Antimicrobial activity of NCL195 against Gram-negative bacteria alone and in combination with EDTA or polymyxin B.</p

NCL812 and NCL195 exhibit high plasma concentration and low plasma clearance rates.

<p>Pharmacokinetic parameters for NCL812 (<b>A</b>) and NCL195 (<b>B</b>) after IV administration at a dose of 5 mg/kg to male CD1 mice (n = 8 per compound), indicating that both compounds exhibited high plasma concentrations and long apparent terminal elimination half-lives. (<b>C</b>), Pharmacokinetic parameters for NCL195 after IP administration at a dose of 43 mg/kg to male CD1 mice (n = 2 per time point), indicating that NCL195 was rapidly absorbed after dosing, and plasma concentrations remained above 3–4 μg/ml for the initial 7.5 h post-dose period.</p

Physicochemical and metabolism parameters for NCL812, NCL195 and NCL219 in human and mouse liver microsomes.

<p>Physicochemical and metabolism parameters for NCL812, NCL195 and NCL219 in human and mouse liver microsomes.</p

MIC range values for NCL812, NCL195 and NCL219 compared to MIC₉₀ values for daptomycin and ampicillin against <i>S</i>. <i>pneumoniae</i>, <i>S</i>. <i>aureus</i> and vancomycin resistant enterococci (VRE).

<p>MIC range values for NCL812, NCL195 and NCL219 compared to MIC₉₀ values for daptomycin and ampicillin against <i>S</i>. <i>pneumoniae</i>, <i>S</i>. <i>aureus</i> and vancomycin resistant enterococci (VRE).</p