Chemical and Microbiologic Aspects of Penems, a Distinct Class of β-Lactams: Focus on Faropenem

Jeremy M. T. Hamilton-Miller, D.Sc., FRCPath

Disclosures

Pharmacotherapy. 2003;23(11) 

In This Article

Structural Classification of Penems

β-lactam antibiotics consist of a four-membered β-lactam ring, which may be fused to five- or six-membered heterocyclic rings (Figure 1). Heterocyclic rings may be saturated or unsaturated with a double bond positioned between positions 3 and 4, and the heteroatom in position 1 may be sulfur (penams, cephems, and penems), carbon (carbapenems and carbacephems), or oxygen (clavams, oxapenems, and oxacephems). The hydrogen atoms at C5 and C6 of the penams, and C6 and C7 of the cephems, are in the cis orientation, whereas the hydrogen atoms at C5 and C6 of carbapenems and penems are in the trans orientation. Monobactams, a structurally distinct class of agents, consist of unfused β-lactam rings.

Representative β-lactam ring structures. Atom numbering is illustrated for penams and cephems.

The structural core of penem molecules is a hybrid of penicillin (penam) and cephalosporin (cephem) structures.[4,5] These hybrid β-lactam structures do not occur naturally, and production of penems is an entirely synthetic process.

Although structurally distinct, the penems are often confused with the carbapenem class of drugs.[6,7] Penems have an unsaturated five-membered thiazoline ring with a double bond positioned between C2 and C3, fused to the β-lactam ring; a sulfur atom occupies position 1 of the heterocyclic ring (Figure 1),[8] altering the three-dimensional shape of the molecule. In contrast, carbapenems are based on the β-lactam ring fused to an unsaturated five-membered pyrolline ring with a carbon atom at position 1.

Five main penem subgroups -- thiopenems, oxypenems, aminopenems, alkylpenems, and arylpenems -- have been produced and are distinguished by the side chain at position 2 of the unsaturated five-membered ring (Figure 2). One structurally distinct penem is BRL 42715 (Figure 2). This molecule has no substitution at position 2 but has a bulky group at position 6, and it displays effective inhibition of class C β-lactamases, but no antimicrobial activity.

Examples of four of the five main penem subgroups and one structurally distinct penem.

One possible consequence of these structural differences of penems from other β-lactams may be reduced immunogenicity and immunogenic cross-reactivity. Up to 10% of the population have an allergy to penicillins,[9] and approximately 10% of these people also have an allergy to cephalosporins.[10] The β-lactam rings of penicillins react with the ε amino group of lysine residues to form penicilloyl-protein antigens. In contrast, when the β-lactam rings of cephalosporins are broken in this way, the ring nucleus of the molecule usually disintegrates, leaving only the side chain at position 7 bound to the protein to determine antigenicity.[11] Penicillins and cephalosporins generally vary through their substitution at position 6 or 7, respectively, with the heterocyclic ring presenting the less variable part of these molecules. In contrast, penems are generally derivatized at position 2 in the heterocyclic ring, making this part of the molecule more variable. For this reason, reduced cross immunogenicity with penicillins and cephalosporins may be expected. Indeed, one study found low levels of cross-reactivity of antibodies against a range of β-lactams to faropenem in a rabbit model.[12]

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