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Drugs for bad bugs: confronting the challenges of antibacterial discovery
TLDR
The experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years is shared, and what is learned is looked at and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
Crystal structure of the IMP-1 metallo beta-lactamase from Pseudomonas aeruginosa and its complex with a mercaptocarboxylate inhibitor: binding determinants of a potent, broad-spectrum inhibitor.
TLDR
A unique mode of binding of the mercaptocarboxylate inhibitor in the enzyme active site provides a binding model for metallo beta-lactamase inhibition with utility for future drug design.
Two Active Forms of UDP-N-Acetylglucosamine Enolpyruvyl Transferase in Gram-Positive Bacteria
TLDR
It was shown that whereas gram-negative bacteria have only one murA gene, gram-positive bacteria have two distinct genes encoding these enzymes which have possibly arisen from gene duplication.
A conserved residue at the extreme C-terminus of FtsZ is critical for the FtsA-FtsZ interaction in Staphylococcus aureus.
TLDR
Using deletion mutagenesis, it is shown that a highly conserved motif as small as 10 residues in the extreme C-terminus of S. aureus FtsZ is critical for the interaction with FtsA, which has important implications for the design of antagonists and agonists of the FTSA-FtsZ interaction.
Characterization of Streptococcus pneumoniae enoyl-(acyl-carrier protein) reductase (FabK).
TLDR
The restricted occurrence of the FabK enoyl-ACP reductase may be related to the role of substrate-independent NADH oxidation in oxygen-dependent anaerobic energy metabolism.
Defining and Combating the Mechanisms of Triclosan Resistance in Clinical Isolates of Staphylococcus aureus
TLDR
Three compounds from a novel chemical series of FabI inhibitors which have excellent activities against both triclosan-resistant and -sensitive clinical isolates of S. aureus are presented.
Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.
TLDR
The hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents is supported, with a new series of inhibitors developed with greatly increased potency against FabI-containing organisms.
Crystal structure of the zinc-dependent beta-lactamase from Bacillus cereus at 1.9 A resolution: binuclear active site with features of a mononuclear enzyme.
TLDR
The broad specificity of this enzyme, together with the increasing prevalence of zinc-dependent metallo-beta-lactamases, poses a real clinical threat, and this structure provides a basis for understanding its mechanism and designing inhibitors.
Challenges of antibacterial discovery revisited
TLDR
Implementing multiple screening and target identification strategies is recommended for improving the likelihood of discovering new antibacterial compounds that address unmet needs, particularly by the identification of new antibiotic classes with improved tractability and by expanding the predictability of in vitro safety assays.
Comparative activities of clavulanic acid, sulbactam, and tazobactam against clinically important beta-lactamases
TLDR
Clavulanic acid was a more potent inhibitor than sulbactam for 32 of the 35 plasmid-mediated beta-lactamases tested and was 60 and 580 times more potent than sul bactam against TEM-1 and SHV-1, respectively, currently the two most clinically prevalent gram-negative plasmids in the world.
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