Tamoxifen induces biochemical responses in Pacific oysters Magallana gigas (Thunberg, 1793) at environmentally relevant concentrations.

The activities of catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), and glutathione-S-transferase (GST) were evaluated in the gills (GI) and digestive gland (DG) of Magallana gigas oysters exposed to tamoxifen (TAM) at environmental concentrations of 10 and 100 ng L-1 for 1 and 4 days. A higher CAT activity in the GI and DG and higher GPx activity only in the DG was observed of oysters exposed to both concentrations after 1 day. Furthermore, a significant increase in GR and G6PDH, was detected in the DG after 1 day of exposure to 10 ng L-1 and only G6PDH activity increase after 1 day of exposure to 10 ng L-1 in the GI. This suggests that the DG is a tissue more sensitive to TAM exposure and was confirmed with the individual Integrated Biomarker Response version 2 index (IBRv2i), highlighting the acute stress caused by TAM and a cellular adaptation.

N-Thio-ß-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis.

Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic ß-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-ß-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-ß-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of LdtMt2. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated in vitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds.