P-Lactamase stability

Ohya S, Yamazaki M, Sugawara S. Effect of 7 a substitution of cephems on their p-lactamase stability and affinity for penicillinbinding proteins in Morganella morganii. Antimicrob Agents Chemother 1983 23(4) 522-525. 

Fig. 10.2 Examples of the side-chain R in various penicillins and mecillinams (the numbers 1-21 correspond to those in Table 10.1). Numbers20 (mecillinam) and21 (pivmecillinam) are6-P-amidinopenicillanicacids (mecillinams). Number 11 (temocillin) has a methoxy (—OCH3) group at position 6a this confers high P-lactamase stability on the molecule.

Although the activity of methoxylated monobactams could be improved by appropriate side-chain modifications, difficulty of synthesis and poor chemical stability focused attention on the nonmethoxylated analogues. Both high intrinsic activity and excellent p-lactamase stability are exhibited by monobactams that combine C-3 aminothiazole oxime side chains and 4-alkyl, 4-alkenyl, and 4-alkynyl groups (19). 

The biological activity of SQ 28,112 (43), shown in Table 4, is typical of the monophosphatams which possess the same spectrum of activity as aztreonam, but have comparatively lower intrinsic activity and P-lactamase stability. 

The use of p-lactam-sensitive mutants, in combination with p-lacta-mases, allows a certain degree of characterization based on p-lactamase stability. 

TABLE XII Relationship of the 7a-Methoxyl Group to p-Lactamase Stability ... 

The compound is reported to be two to four times more active than cefoxitin and equally stable to (3-lactamases. The p-lactamase stability of this compound compared with that of cefoxitin and a range of cephalosporins is shown in Table XIV. Structure-activity studies bearing on this molecule have been conducted by Nakao et al. (1979). 

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