Biomedical Engineering Reference
In-Depth Information
b-Lactam antibiotics inhibit transpeptidase and carboxypeptidase. In this reaction, the b-lactam
ring is opened and the serine of catalytic part of the enzyme is acylated. The inhibition of the cross-
linking reaction yields a poorly structured cell wall and results in the lysis of the cell. This explains
the early observation that penicillin affects only growing bacteria.
From 1972 onward, several investigators could show, using radioactive penicillin and separa-
tion techniques, that membranes of bacteria contained several penicillin-binding proteins (PBPs).
Differences in susceptibility of bacteria to different b-lactams may be explained by the amounts
of the different PBPs and their afi nity for these antibiotics. The PBP of lower molecular mass
are monofunctional carboxy- and endopeptidases, transpeptidases, and b-lactamase. The higher
molecular mass PBPs are multimodular containing a transpeptidase and, for example, a transglyco-
sylase. It seems that inhibition of at least two PBPs is required for efi cient killing by b-lactams.
In the periplasmic space (between cytoplasmic membrane and outer membrane), several enzymes
are present, e.g., b-lactamases (in all Gram-negative bacteria), enzymes that acetylate chloram-
phenicol, adenylate streptomycin, etc. and also proteins responsible for the transport of sugars and
other nutrients.
In Gram-negative bacteria, antibiotics have to pass through the porins. This permeation is easi-
est for polar molecules. A second factor in their activity is the resistance to b-lactamase. A third
factor, both in Gram-positive and Gram-negative bacteria is the afi nity for PBP. There are marked
differences in this afi nity for different penicillins and cephalosporins. The minimum inhibitory
concentration (MIC) that measures the in vitro activity of an antibiotic is the result of a series of
different factors.
25.7 MEMBRANES
The cytoplasmic membrane of bacteria is also a lipoprotein structure. The major phospholipid is
phosphatidylethanolamine. Several proteins (also enzymes) are located in and around this mem-
brane. Polymyxin and colistin interact with the cell membrane. The binding of the drug involves the
phosphate groups of the phospholipid. According to a mechanism similar to that of the quaternary
ammonium detergents, the fatty acid tail penetrates into the hydrocarbon part of the phospholipid,
while the cyclic peptide containing the free amino groups interacts with the phosphate groups. This
disruption of the membrane structure brings about a loss of their permeability barrier property.
Biochemical functions like respiration, nucleic acid and protein synthesis are perturbed. Tyrocidine
that does not have a detergent-like structure nevertheless has a similar effect.
Ionophores cause the loss of essential monovalent cations (K + ) because of specii c changes in the
permeability of the membrane. The polyethers act as carriers, by providing lipid solubility of the
transported cations. Gramicidin, which is a linear peptide, probably adopts a helical conformation
and forms a hydrophobic channel of the ions.
25.8 NUCLEIC ACID SYNTHESIS
The planar phenoxazone ring of actinomycin intercalates at the level of GpC sequences in DNA.
This intercalation partially unwinds the DNA helix and inhibits the use of DNA for replication and
transcription. The anthracycline antibiotics have a more complex mode of action: they intercalate
in DNA, they have alkylating properties, they inhibit the action of topoisomerase II and could give
rise to hydroxyl radicals that damage DNA. Several antitumoral antibiotics like daunomycin and
bleomycin may break strands of DNA and give rise to cross-linking. Rifampicin inhibits RNA
polymerase by directly binding to the enzyme in a noncovalent manner. The drug does not inhibit
transcription once it has begun, but prevents the initiation of the transcription.
A molecule of DNA consists of two linear strands intertwined to form a double helix. Those
strands form often a ring. Such a relaxed bacterial DNA is too long to i t inside a bacterial cell.
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