OXA-207, a novel OXA-24 variant with reduced catalytic efficiency against carbapenems in Acinetobacter pittii from Spain

A carbapenem-resistant Acinetobacter pittii strain carrying an OXA-24-like enzyme was isolated in northern Spain in 2008. Sequence analysis confirmed the presence of the novel bla(OXA-207) gene flanked by the site-specific XerC/XerD-like recombination binding sites and showing a unique Gly222Val substitution compared to OXA-24. Cloning and kinetic analysis showed that OXA-207 presents a reduction in the catalytic efficiency against carbapenems and a noticeable increase for oxacillin

Endemic Carbapenem Resistance Associated with OXA-40 Carbapenemase among Acinetobacter baumannii Isolates from a Hospital in Northern Spain

Eighty-two carbapenem-resistant isolates of Acinetobacter baumannii from a single hospital in Bilbao were typed into two major clusters and several subclusters. Disk synergy tests and PCR indicated the production of a zinc-independent OXA-class carbapenemase. Sequencing identified this enzyme, OXA-40, as a variant of the OXA-24-OXA-25-OXA-26 cluster

OXA-198, an Acquired Carbapenem-Hydrolyzing Class D β-Lactamase from Pseudomonas aeruginosa▿

A carbapenem-resistant Pseudomonas aeruginosa strain (PA41437) susceptible to expanded-spectrum cephalosporins was recovered from several consecutive lower-respiratory-tract specimens of a patient who developed a ventilator-associated pneumonia while hospitalized in an intensive care unit. Cloning experiments identified OXA-198, a new class D β-lactamase which was weakly related (less than 45% amino acid identity) to other class D β-lactamases. Expression in Escherichia coli TOP10 and in P. aeruginosa PAO1 led to transformants that were resistant to ticarcillin and showed reduced susceptibility to carbapenems and cefepime. The blaOXA-198 gene was harbored by a class 1 integron carried by a ca. 46-kb nontypeable plasmid. This study describes a novel class D β-lactamase involved in carbapenem resistance in P. aeruginosa

Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis

BACKGROUND & AIMS: Glycine N-methyltransferase (GNMT) expression is decreased in some patients with severe NAFLD. Gnmt deficiency in mice (Gnmt-KO) results in abnormally elevated serum levels of methionine and its metabolite S-adenosylmethionine (SAMe), and this leads to rapid liver steatosis development. Autophagy plays a critical role in lipid catabolism (lipophagy), and defects in autophagy have been related to liver steatosis development. Since methionine and its metabolite SAMe are well known inactivators of autophagy, we aimed to examine whether high levels of both metabolites could block autophagy-mediated lipid catabolism. METHODS: We examined methionine levels in a cohort of 358 serum samples from steatotic patients. We used hepatocytes cultured with methionine and SAMe, and hepatocytes and livers from Gnmt-KO mice. RESULTS: We detected a significant increase in serum methionine levels in steatotic patients. We observed that autophagy and lipophagy were impaired in hepatocytes cultured with high methionine and SAMe, and that Gnmt-KO livers were characterized by an impairment in autophagy functionality, likely caused by defects at the lysosomal level. Elevated levels of methionine and SAMe activated PP2A by methylation, while blocking PP2A activity restored autophagy flux in Gnmt-KO hepatocytes, and in hepatocytes treated with SAMe and Methionine. Finally, normalization of methionine and SAMe levels in Gnmt-KO mice using a methionine deficient diet normalized the methylation capacity, PP2A methylation, autophagy, and ameloriated liver steatosis. CONCLUSIONS: These data suggest that elevated levels of methionine and SAMe can inhibit autophagic catabolism of lipids contributing to liver steatosis