it is very unstable and therefore unlikely to be of use in its native form. The N-formimidyl
derivative overcomes this problem.
Clavulanic acid (9.39), which is produced by a Streptomyces species, has only weak
antibiotic activity but is a potent β-lactamase inhibitor. It can therefore protect lactamase-
sensitive but otherwise potent antibiotics (e.g., ampicillin) from deactivation.
The monocyclic nocardicins represent the ultimate “simplification” of the β-lactam
structure, containing the azetidinone ring by itself, with a side chain resembling that of
cephalosporin C. Nocardicin A (9.54), the (Z)-oxime, has limited activity against some
Gram-negative bacteria. The similar aztreonam (9.55) is active against Gram-negative
bacteria and Pseudomonas,and is lactamase resistant.
9.4.1.4 β-Lactam Structure–Activity Correlations
Structure–activity correlations in the β-lactam antibiotic field have required drastic
re-evaluation in view of the novel structures described above. Apparently, only the intact
β-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced
(moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unneces-
sary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by
a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase
resistance. The amide side chain, so widely varied in the past, is also unnecessary, as
shown in the example of thienamycin. There is a considerable literature analyzing the
classical structure–activity relationships of the penicillin and cephalosporin groups.
9.4.2 Antibacterials Targeting Bacterial Cell MembranesSome microorganisms produce compounds that can become incorporated into lipid
membranes and will facilitate the transmembrane transport of ions, notably K+. These
natural products are antibacterial, killing bacteria by lethally altering the transmem-
brane ion flux. Such antibacterial molecules are called ionophores, or ion carriers, in
contrast to other antibacterials, such as polyene antibiotics, which simply produce leak-
age through the cell membrane.
Ionophoric antibiotics can function either as “cage” carriers of an ion or as channel
formers. The cage carrier encloses an ion and transports it from one side of the membrane
EXOGENOUS PATHOGENS AND TOXINS 569