Penicillins and Others, β‐Lactams

Abstract

The basic structural features of the penicillin nucleus include a β‐lactam ring fused through nitrogen and the adjacent tetrahedral carbon to a second heterocycle which, in natural penicillin, is a 5‐membered thiazolidine ring. Biologically active penicillins are generally characterized by a functionalized amino group in the 6β‐position of the β‐lactam ring and a carboxyl group in the 3‐position in the thiazolidine ring. The unsubstituted bicyclic ring system of the penicillins is designated as penam, C 5 H 7 NOS and the penicillins are generally 6‐acylamino‐2,2‐dimethylpenam‐3‐carboxylic acids. In general, penicillins exert their biological effect, as do the other β‐lactams, by inhibiting the synthesis of essential structural components of the bacterial cell wall. These components are absent in mammalian cells so that inhibition of the synthesis of the bacterial cell wall structure occurs with little or no effect on mammalian cell metabolism. Additionally, penicillins tend to be irreversible inhibitors of bacterial cell‐wall synthesis and are generally bactericidal at concentrations close to their bacteriostatic levels. Consequently penicillins have become widely used for the treatment of bacterial infections and are regarded as one of the safest and most efficacious classes of antibiotics. Penicillins in clinical use include limited spectrum penicillins [benzyl penicillin (penicillin G) (C 16 H 18 N 2 O 4 S), phenoxymethyl penicillin (penicillin V) (C 16 H 18 N 2 O 5 S), and phenethicillin ( \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{_{17}}{\rm{H}} _{20}{\rm{N}}{_{2}}{\rm{O}}{_{5}}{\rm{S}}{\rm{{\cdot{}}}}{\rm{K}}}$\end{document} ], β‐lactamase stable penicillins [methicillin ( \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{_{17}}{\rm{H}} _{20}{\rm{N}}{_{2}}{\rm{O}}{_{6}}{\rm{S}}{\rm{{\cdot{}}}}{\rm{Na}}}$\end{document} , oxacillin (C 19 H 19 N 3 O 5 S), cloxacillin (C 19 H 18 ClN 3 O 5 S), dicloxacillin (C 19 H 17 Cl 2 N 3 O 5 S), flucloxacillin (C 19 H 17 ClFN 3 O 5 S), and nafcillin (C 21 H 22 N 2 O 5 SNa)], broad spectrum penicillins [ampicillin (C 16 H 19 N 3 O 4 S), hetacillin (C 19 H 23 N 3 O 4 S), pivampicillin (C 22 H 29 N 3 O 6 S), talampicillin (C 24 H 23 N 3 O 6 S), bacampicillin (C 21 H 27 N 3 O 7 S), ciclacillin (C 15 H 23 N 3 O 4 S), amoxicillin (C 16 H 19 N 3 O 5 S), carbenicillin (C 17 H 18 N 2 O 6 S), ticarcillin (C 15 H 16 N 2 O 6 S 2 ), sulbenicillin (C 16 H 18 N 2 O 7 S 2 ), azlocillin (C 20 H 23 N 5 O 6 S), mezlocillin (C 21 H 25 N 5 O 8 S 2 ), and piperacillin (C 23 H 27 N 5 O 7 S)], and directed spectrum β‐lactamase stable penicillins [temocillin (C 16 H 18 N 2 O 7 S)]. Penicillins have several properties characteristic of β‐lactam antibiotics. They are obtained in relatively pure form as off‐white, tan, or yellow freeze‐dried or spray‐dried solids that are usually amorphous. Alternatively they are sometimes obtained as crystalline solids, often as hydrates. Penicillins do not usually have sharp melting points, but decompose upon heating to elevated temperatures. Penicillin G, penicillin V, and 6‐APA have proven to be cheap and versatile starting materials for a number of conversions to novel β‐lactam systems including 7‐aminodeacetoxycephalosporanic acid (7‐ADCA), the deacetoxycephalosporins, cephalexin and cephradin, moxalactam and related oxacephems, novel penems, and the carbapenem antibiotic thienamycin. The only penicillins used in their natural form are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). The remainder of penicillins in clinical use are derived from 6‐APA and most penicillins having useful biological properties have resulted from acylation of 6‐APA using standard procedures. Chemical modification of most positions in the penicillin nucleus have been carried out. One of the modifications that has led to beneficial properties is substitution at the 6α‐position. Penicillins are rapidly hydrolyzed by aqueous alkali to the corresponding penicilloic acids which are stable as salts, but which decarboxylate on acidification to yield penilloic acids. Penicillin G remains probably the most active penicillin against gram‐positive organisms. However, the majority of Staphylococcus aureus strains are resistant to penicillin by virtue of β‐lactamase production. The β‐lactamase‐resistant penicillins such as oxacillin, cloxacillin, flucloxacillin, and nafcillin are active against most penicillin‐resistant Staphylococci but lack activity against methicillin‐resistant Staphylococci (MRSA) and the majority of gram‐negative organisms. Ampicillin and its congeners amoxicillin, bacampicillin, and ciclacillin, have largely similar antibacterial spectra, exhibiting activity against both penicillin‐sensitive gram‐positive and gram‐negative microorganisms. The susceptibility of ampicillin or amoxicillin to β‐lactamase may be overcome by combination with a β‐lactamase inhibitor such as clavulanic acid and sulbactam. Temocillin is the first penicillin to possess a high level of activity against gram‐negative organisms, notably the Enterobacteriaceae, as well as excellent β‐lactamase stability. BRL 36650 is highly potent against most gram‐negative organisms including refractory gram‐negative species such as Acinetobacter and Pseudomonas. The level of potency is much greater than either that of ticarcillin or piperacillin. The pharmacology of penicillins differs markedly from compound to compound. The majority of derivatives, including penicillin G and the antipseudomonal penicillins, are unstable in gastric acid and are not available orally. Penicillin V, ampicillin, and particularly amoxicillin are relatively well absorbed orally. The penicillins in general are renowned for their lack of toxicity. The most common adverse effect of the use of penicillins is an allergic reaction which can change from a mild rash to fatal anaphylactic shock in rare cases. Penicillins exert their antibacterial effect by inhibiting the high molecular weight penicillin‐binding proteins (PBPs) that are implicated in the final stages of peptidoglycan synthesis. Most methods used for the production of the commercially important α‐amino penicillins are based on modifications of an enamine process employing the appropriate phenylglycine and methylacetoacetate followed by coupling with 6‐APA.