such as the penicillins and cephalosporins, after the bacterium has expended considerable
biosynthetic energy. In contrast to this inhibition of the last step of a reaction sequence,
the feedback inhibition of enzymatic reactions normally occurs at the first step in a
sequence, avoiding any wastage of precursor substances; if it occurs late, biochemical
efficiency is seriously jeopardized.
Various investigations have elucidated many details of this process. First, the
antibacterial agent has to penetrate the outer membrane of the Gram-negative bacteria,
which are less susceptible to antibiotics. This membrane consists of lipopolysaccha-
rides, phospholipids, lipoproteins, and proteins. The β-lactam antibiotics (penicillins,
cephalosporins) cross this diffusion-resistant membrane through porin channels,
trimeric proteins that traverse the membrane. There are about 10^5 channels per bacterial
cell, and their diameter is 1.2 nm. Some bacterial genera (e.g.,Pseudomonas) are insen-
sitive to most β-lactamantibiotics because the majority of their porin channels are not
functional. The next hurdle the antibiotic has to surmount involves the β-lactamase
enzymes in the periplasmic space, between the outer and inner membranes; these
can deactivate the antibiotic (Gram-positive bacteria excrete the lactamase into the
medium). Beyond that is the peptidoglycan cell wall with the associated penicillin-
binding proteins, which are the essential transpeptidases, transglycosylases, and
D-alanine carboxykinases involved in cell wall synthesis. Penicillin (9.37) inactivates
these by acylation of the active sites, as a “suicide substrate.” Different transpeptidases
have different roles in the cell, and their selective inactivation can lead to cell lysis or
production of deformed (spherical or threadlike) cells as well as cell wall synthesis
inhibition.
9.4.1.1 Penicillins
The penicillins (or penams) were discovered in 1929 by Sir Alexander Fleming, and
developed by Florey, Chain, and Abraham at Oxford University. The history of
penicillin became a story of legendary proportions, illustrating the case of a serendipi-
tous discovery combined with brilliant development; it also marks the beginning of the
modern chemotherapy of infectious diseases.
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