Chapter 15 : γ-Lactams and Derivatives

Abstract:

The β-lactams represent the largest clinical class of antibiotics. Interest has since turned to the pentacycles, which possess certain affinities for penicillin-binding proteins (PBP), such as the γ-lactams, pyrazolidinones, and isoxazolidinones (lactivicin). The first γ-lactams molecules to exhibit antibacterial activity were described in 1986. The first derivative, derivative A, is active against Staphylococcus aureus. The opening of the γ-lactam ring is dependent on the substituent at C-3. The increase in lipophilicity of the substituent at C-3 or on the oxime residue enhanced the activity against gram-positive bacteria but decreased that against gram-negative bacteria. Lactivicin is an antibacterial agent isolated from the fermentation of Empedobacter lactamgenus YK-258 and Lysobacter albus YK-422. Lactivicin is an acidic antibiotic that is soluble in water. The physicochemical properties of lactivicin and the methylated esters of the carboxyl group are summarized. Lactivicin is active against gram-positive bacteria and inactive against gram-negative bacteria. The mechanism of action of lactivicin is similar to that of the β-lactams. Synthetic derivatives have been prepared to reduce the parenteral toxicity and to increase the activity and antibacterial spectrum. The acute toxicity is 400 mg/kg of body weight subcutaneously and more than 400 mg/kg orally. The lack of the γ-lactam nucleus suppresses the antibacterial activity. Derivatives with a D-phenylglycyl group are inactive because they are unstable in a neutral or basic medium.