Matteo Pori

Persistence and degradation of new β-lactam antibiotics in the soil and water environment.

The development of new antibiotics with low environmental persistence is of utmost importance in contrasting phenomena of antibiotic resistance. In this study, the persistence of two newly synthesized monocyclic β-lactam antibiotics: (2R)-1-(methylthio)-4-oxoazetidin-2-yl acetate, P1, and (2R,3R)-3-((1R)-1-(tert-butyldimethylsilanyloxy)ethyl)-1-(methylthio)-4-oxoazetidin-2-yl acetate, P2, has been investigated in water in the pH range 3-9 and in two (calcareous and forest) soils, then compared to amoxicillin, a β-lactam antibiotic used in human and veterinary medicine. P1 and P2 persistence in water was lower than that of amoxicillin with only a few exceptions. P1 hydrolysis was catalyzed at an acidic pH whereas P2 hydrolysis takes place at both acidic and alkaline pH values. P1 persistence in soils depended mainly on their water potential (t1/2: 35.0-70.7d at wilting point; <1d at field capacity) whereas for P2 it was shorter and unaffected by soil water content (t1/2 0.13-2.5d). Several degradation products were detected in soils at both water potentials, deriving partly from hydrolytic pathways and partly from microbial transformation. The higher LogKow value for P2 compared with P1 seemingly confers P2 with high permeability to microbial membranes regardless of soil water content. P1 and P2 persistence in soils at wilting point was shorter than that of amoxicillin, whereas it had the same extent at field capacity.

Monocyclic β-lactams as antibacterial agents: Facing antioxidant activity of N-methylthio-azetidinones

A series of N-methylthio-β-lactams with antibacterial activity were thoroughly evaluated as antioxidants. We found that only the presence of a polyphenolic moiety anchored to the β-lactam ring ensured an adequate antioxidant potency. New compounds, efficiently combining in one structure antioxidant and antibacterial activity, may provide a promising basis for the development of new leads useful in adverse clinical conditions such as in cystic fibrosis patients, in whom colonization by MRSA and epithelial damage by chronic pulmonary oxidative stress take place.

Antibacterial Agents and Cystic Fibrosis: Synthesis and Antimicrobial Evaluation of a Series of N-Thiomethylazetidinones

The increasing emergence of multidrug‐resistant microorganisms is one of the greatest challenges in the clinical management of infectious disease. New antimicrobial agents are therefore urgently required, particularly in the treatment of chronic and recurrent infections often associated with antibiotic‐resistant pathogens, as in the case of cystic fibrosis (CF) patients. This study reports the antibacterial activity of a series of monocyclic β‐lactams with an alkylidenecarboxyl chain or electron‐withdrawing groups such as 4‐OAc, 4‐SAc, and 4‐SO2Ph at the C4 position of the ring. N‐Unsubstituted and N‐thiomethyl derivatives were compared. A total of 33 azetidinones were tested for their activity against Gram‐positive and Gram‐negative bacterial clinical isolates. The combination of an N‐thiomethyl group and a benzyl ester on the 4‐alkylidene side chain were found to increase the potency against Gram‐positive bacteria. The N‐thiomethyl group clearly elevated the activity of 4‐acetoxyazetidinones relative to the corresponding NH derivatives. The most active compounds showed minimum inhibitory concentration (MIC) values of 4 and 8 mg L−1 against methicillin‐resistant Staphylococcus aureus isolated from pediatric patients with CF.

Laccase-mediator system for alcohol oxidation to carbonyls or carboxylic acids: toward a sustainable synthesis of profens.

By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration.

Azetidinone-retinoid hybrids: synthesis and differentiative effects.

As a part of a systematic investigation on the synthesis and biological activities of new β-lactam compounds, we examined β-lactam candidates 1, 2E and 2Z and their ability to induce cell proliferation or differentiation. Azetidinone 1 was chosen for its activity (previously evaluated) as selective HDAC8 inhibitor, whereas β-lactams 2E and 2Z were designed to have a hybrid retinoid-azetidinone structure, de novo synthesized and fully characterized. Biological activities were determined in cellular assays on neuroblastoma cells SH-SY5Y. Azetidinone 1, 2E and 2Z led to a moderate effect in decreasing SH-SY5Y cell proliferation and β-lactams 2E and 2Z induced an early stage differentiation. The present results uncovered a new role of specifically designed β-lactam compounds in epigenetic regulation.