Penicillins and Mechanisms of Bacterial Resistance. The most serious threat to
antibiotic therapy, and to the use of β-lactam antibiotics in particular, is the emergence
of resistant bacterial strains. The primary reason for this resistance is the production of
an enzyme,β-lactamase (penicillinase), which in Gram-positive bacteria is excreted
into the growth medium but in Gram-negative bacteria remains contained in the cell.
Thus, Gram-positive organisms quickly destroy the antibiotic in the surrounding solution
by hydrolysis, converting it to the inactive penicilloic acid. Since production of peni-
cillinase enzymes is under plasmid control, resistant bacteria can transfer their resis-
tance. Hence, bacterial species that were in the past easily controlled with penicillin
have increasingly become a serious medical problem.
Inhibitors of β-lactamase are known. The synthetic sulfone tazobactam (9.38), and
clavulanic acid (9.39) both have weak antibacterial activity besides β-lactamase inhibitory
activity, and they can be used in combination with vulnerable antibiotics.
Semisynthetic Penicillins.However useful they may be, natural penicillins have
several drawbacks. They have a relatively narrow activity spectrum, primarily inhibit-
ing Gram-positive bacteria only. They are acid- and lactamase-sensitive, and in a small
percentage of patients they cause allergic side effects. All of these limitations could
potentially be overcome by molecular modifications during the biosynthesis of these
drugs. Unfortunately, however, the fermentation process used in penicillin production
is not very flexible and does not permit the incorporation of very many amide side
chains into the molecule.
Although the total synthesis of penicillins was accomplished by Sheehan and his
co-workers in 1953, and although some other approaches have also been successful, the
syntheses are of limited practical value; nevertheless, they do allow modification of the
ring system.
On the other hand, the discovery of the parent amine 6-aminopenicillanic acid (9.40,
6-APA) in fermentation products constituted a major breakthrough in penicillin synthesis.
566 MEDICINAL CHEMISTRY