6- Aminopenicillanic acid, -lactamases

The penicillins [pen i SILL in] are the most widely effective antibiotics and are among the least toxic drugs known the major adverse reaction to penicillins is hypersensitivity. The members of this family differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue. The nature of this side chain affects their antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (P-lactamases). Figure 30.1 shows the main structural features of the penicillins. Figure 30.2 shows the classification of agents affecting cell wall synthesis. 

The major penicillin produced by P. chrysogenum in submerged culture was benzylpenicillin (PenG) (Figure 4), which was rather unstable under acid conditions and also deactivated by P-lactamases. However, the discovery of 6-aminopenicillanic acid (6-APA) also produced by P. chrysogenum, led to the preparation of new semisynthetic derivatives with improved stability e.g. methicillin, ampicillin and amoxycillin (Figure... 

All penicillins (Fignre 74) are composed of a thiazolidine ring attached to a beta-lactam, which in turn carries a free amide gronp (0=CNH) on which a substitution and an attachment (R) are made. In the case of benzylpenicillin, the R is a benzyl gronp. Penicillin may be metabolized by amidase to 6-aminopenicillanic acid, which has antibacterial activity, or by penicillinase (bacterial beta-lactamase), to penicilloic acid, which is devoid of antibacterial activity bnt is antigenic in natnre and acts as a sensitizing structure. The main sonrce of bacterial resistance to penicillin is in fact the prodnction of penicillinase by the microorganisms. 

Application of structurally similar lactams that are bactericidal and that are not hydrolysed by y0-lactamase [106]. A few semisynthetic penicillins fulfil these requirements. For instance, 6-amino-2,2-dimethyl-7-oxopenam-3-carboxylic acid (also known as 6-aminopenicillanic acid) can be prepared from a natural penicillin. This is then converted into a penicillin by acylation with another residue R. One of the most effective compounds of this type is ampicillin. 

Fig. 15.21. (bottom curve). 6-Aminopenicillanic acid after -lactamase hydrolysis. (Holt and Stewart, 1965.)... 

Patil and Day described the irreversible inactivation of /8-Iactamase from B. cereus 569/H with diazotization products of 6-aminopenicillanic acid and ampicillin. Preliminary experiments and jS-lactamasers and the diazotization products from many penicillins and cephalosporins showed no inactivation. 

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