In vitro and intracellular activity of vaborbactam combined with β-lactams against Mycobacterium abscessus.

Objectives: Mycobacterium abscessus has emerged as an opportunistic pathogen responsible for lung infections, especially in cystic fibrosis patients. In spite of the production of the broad-spectrum β-lactamase BlaMab, the carbapenem imipenem is recommended in the initial phase of the treatment of pulmonary infections. Here, we determine whether the addition of vaborbactam, a second-generation β-lactamase inhibitor belonging to the boronate family, improves the activity of β-lactams against M.

Amino-acyl tXNA as inhibitors or amino acid donors in peptide synthesis.

Xenobiotic nucleic acids (XNAs) offer tremendous potential for synthetic biology, biotechnology, and molecular medicine but their ability to mimic nucleic acids still needs to be explored. Here, to study the ability of XNA oligonucleotides to mimic tRNA, we synthesized three L-Ala-tXNAs analogs. These molecules were used in a non-ribosomal peptide synthesis involving a bacterial Fem transferase.

Role of endopeptidases in peptidoglycan synthesis mediated by alternative cross-linking enzymes in Escherichia coli.

Bacteria resist to the turgor pressure of the cytoplasm through a net-like macromolecule, the peptidoglycan, made of glycan strands connected via peptides cross-linked by penicillin-binding proteins (PBPs). We recently reported the emergence of β-lactam resistance resulting from a bypass of PBPs by the YcbB L,D-transpeptidase (LdtD), which form chemically distinct 3→3 cross-links compared to 4→3 formed by PBPs. Here we show that peptidoglycan expansion requires controlled hydrolysis of cross-links and identify among eight endopeptidase paralogues the minimum enzyme complements essential for bacterial growth with 4→3 (MepM) and 3→3 (MepM and MepK) cross-links.

Ceftazidime-Avibactam Resistance Mediated by the NY Substitution in Various AmpC β-Lactamases.

Chromosomal and plasmid-borne AmpC cephalosporinases are a major resistance mechanism to β-lactams in and The new β-lactamase inhibitor avibactam effectively inhibits class C enzymes and can fully restore ceftazidime susceptibility. The conserved amino acid residue Asn of AmpC cephalosporinases directly interacts with the avibactam sulfonate. Disruption of this interaction caused by the NY amino acid substitution in AmpC was previously shown to confer resistance to the ceftazidime-avibactam combination (CAZ-AVI).

Inhibition Activity of Avibactam against Nocardia farcinica β-Lactamase FAR.

, one of the most frequent pathogenic species responsible for nocardiosis, is characterized by frequent brain involvement and resistance to β-lactams mediated by a class A β-lactamase. Kinetic parameters for hydrolysis of various β-lactams by FAR from strain IFM 10152 were determined by spectrophotometry revealing a high catalytic activity (/ ) for amoxicillin, aztreonam, and nitrocefin. For cephems, / was lower but remained greater than 10 M s A low catalytic activity was observed for meropenem, imipenem, and ceftazidime hydrolysis.

Combination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination.

Single amino acid substitutions in the Ω loop of KPC β-lactamases are known to lead to resistance to the ceftazidime-avibactam combination. Here, we investigate this mechanism of resistance in CTX-M enzymes, which are the most widely spread extended-spectrum β-lactamases worldwide. Nine single amino acid polymorphisms were identified in the Ω loop of the 172 CTX-M sequences present in the Lahey database of β-lactamases.

In vitro activity of tedizolid against the Mycobacterium abscessus complex.

Infections due to Mycobacterium abscessus carry a poor prognosis since this rapidly growing mycobacterium is intrinsically resistant to most antibiotics. Here, we evaluate the in vitro activity of the new oxazolidinone tedizolid against a collection of 44M. abscessus clinical isolates.

Bactericidal and intracellular activity of β-lactams against Mycobacterium abscessus.

Objectives: Cefoxitin and imipenem are the sole recommended β-lactams for the treatment of Mycobacterium abscessus pulmonary infections. Here, we investigated whether one of these drugs displays superiority in terms of killing and intracellular activity. We have also evaluated whether the use of a β-lactamase inhibitor could improve their activity.

β-Lactamase inhibition by avibactam in Mycobacterium abscessus.

Objectives: Two β-lactams, cefoxitin and imipenem, are part of the reference treatment for pulmonary infections with Mycobacterium abscessus. M. abscessus has recently been shown to produce a broad-spectrum β-lactamase, BlaMab, indicating that the combination of β-lactams with a BlaMab inhibitor may improve treatment efficacy.

Novel transgenic mice for inducible gene overexpression in pancreatic cells define glucocorticoid receptor-mediated regulations of beta cells.

Conditional gene deletion in specific cell populations has helped the understanding of pancreas development. Using this approach, we have shown that deleting the glucocorticoid receptor (GR) gene in pancreatic precursor cells leads to a doubled beta-cell mass. Here, we provide genetic tools that permit a temporally and spatially controlled expression of target genes in pancreatic cells using the Tetracycline inducible system.