We have developed compounds with a promising activity
against Acinetobacter baumannii and Pseudomonas
aeruginosa, which are both on the WHO priority list
of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold
improved aqueous solubility, a 10-fold improved inhibition of topoisomerase
IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of
human topoisomerase IIα, and no cross-resistance to novobiocin.
Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed
their binding to the ATP-binding pocket of the GyrB subunit. In further
optimization steps, solubility, plasma free fraction, and other ADME
properties of 27 were improved by fine-tuning of lipophilicity.
In particular, analogs of 27 with retained anti-Gram-negative
activity and improved plasma free fraction were identified. The series
was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial
toxicity, and possessed no ion channel liabilities.
O-GlcNAcylation is an essential post-translational modification installed by the enzyme O-β-N-acetyl-d-glucosaminyl transferase (OGT). Modulating this enzyme would be extremely valuable to better understand its role in the development of serious human pathologies, such as diabetes and cancer. However, the limited availability of potent and selective inhibitors hinders the validation of this potential therapeutic target. To explore new chemotypes that target the active site of OGT, we performed virtual screening of a large library of commercially available compounds with drug-like properties. We purchased samples of the most promising virtual hits and used enzyme assays to identify authentic leads. Structure-activity relationships of the best identified OGT inhibitor were explored by generating a small library of derivatives. Our best hit displays a novel uridine mimetic scaffold and inhibited the recombinant enzyme with an IC50 value of 7 µM. The current hit represents an excellent starting point for designing and developing a new set of OGT inhibitors that may prove useful for exploring the biology of OGT.
A new series of dual low nanomolar benzothiazole inhibitors
of
bacterial DNA gyrase and topoisomerase IV were developed. The resulting
compounds show excellent broad-spectrum antibacterial activities against
Gram-positive
Enterococcus faecalis
,
Enterococcus faecium
and multidrug
resistant (MDR)
Staphylococcus aureus
strains [best compound minimal inhibitory concentrations (MICs):
range, <0.03125–0.25 μg/mL] and against the Gram-negatives
Acinetobacter baumannii
and
Klebsiella
pneumoniae
(best compound MICs: range, 1–4
μg/mL). Lead compound
7a
was identified with favorable
solubility and plasma protein binding, good metabolic stability, selectivity
for bacterial topoisomerases, and no toxicity issues. The crystal
structure of
7a
in complex with
Pseudomonas
aeruginosa
GyrB24 revealed its binding mode at the
ATP-binding site. Expanded profiling of
7a
and
7h
showed potent antibacterial activity against over 100 MDR
and non-MDR strains of
A. baumannii
and several other Gram-positive and Gram-negative strains. Ultimately,
in vivo efficacy of
7a
in a mouse model of vancomycin-intermediate
S. aureus
thigh infection was also demonstrated.
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an innate immune pattern recognition receptor responsible for the recognition of bacterial peptidoglycan fragments. Given its central role in the formation of innate and adaptive immune responses, NOD2 represents a valuable target for modulation with agonists and antagonists. A major challenge in the discovery of novel small-molecule NOD2 modulators is the lack of a co-crystallized complex with a ligand, which has limited previous progress to ligand-based design approaches and high-throughput screening campaigns. To that end, a hybrid docking and pharmacophore modeling approach was used to identify key interactions between NOD2 ligands and residues in the putative ligand-binding site. Following docking of previously reported NOD2 ligands to a homology model of human NOD2, a structure-based pharmacophore model was created and used to virtually screen a library of commercially available compounds. Two compounds, 1 and 3, identified as hits by the pharmacophore model, exhibited NOD2 antagonist activity and are the first small-molecule NOD2 modulators identified by virtual screening to date. The newly identified NOD2 antagonist scaffolds represent valuable starting points for further optimization.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.