Page 263 - Color Atlas of Biochemistry

P. 263

254 Molecular genetics

Antibiotics synthesizedbyfungi andhavea reactive β-
lactam ring. They are mainly used against
Gram-positive pathogens, in which they in-
A. Antibiotics: overview
hibit cell wall synthesis (C).
Antibiotics are substances which, even at low The first synthetic antibiotics were the
concentrations, inhibit the growth and repro- sulfonamides (right). As analogues of p–ami-
duction of bacteria and fungi. The treatment nobenzoic acid, these affect the synthesis of
of infectious diseases would be inconceivable folic acid, an essential precursor of the coen-
today without antibiotics. Substances that zyme THF (see p. 108). Transport antibiotics
only restrict the reproduction of bacteria are (top center) have the properties of ion chan-
described as having bacteriostatic effects (or nels (see p. 222). When they are deposited in
fungistatic for fungi). If the target cells are the plasma membrane, it leads to a loss of ions
killed, then the term bactericidal (or fungici- that damages the bacterial cells.
dal) is used. Almost all antibiotics are pro-
duced by microorganisms—mainly bacteria
of the genus Streptomyces and certain fungi. B. Intercalators
However, there are also synthetic antibacte- The effects of intercalators (see also p. 262)
rial substances, such as sulfonamides and gy- areillustrated hereusing theexample of the
rase inhibitors. daunomycin–DNA complex,in which two
A constantly increasing problem in antibi- daunomycin molecules (red) are inserted in
otic treatment is the development of resistant the double helix (blue). The antibiotic’s ring
pathogens that no longer respond to the system inserts itself between G/C base pairs
drugs available. The illustration shows a few (bottom), while the sugar moiety occupies the
of the therapeutically important antibiotics minor groove in the DNA (above). This leads
and their sites of action in the bacterial me- to a localized change of the DNA conforma-
tabolism. tion that prevents replication and transcrip-
Substances known as intercalators,suchas tion.
rifamycin and actinomycin D (bottom) are de-
positedin the DNA double helix andthereby
interfere with replication and transcription C. Penicillin as a “suicide substrate”
(B). As DNA is the same in all cells, intercalat- Thesiteofaction inthe β–lactam antibiotics is
ing antibiotics are also toxic for eukaryotes, muramoylpentapeptide carboxypeptidase, an
however. They are therefore only used as cy- enzyme that is essential for cross–linking of
tostatic agents (see p. 402). Synthetic inhib- bacterial cell walls. The antibiotic resembles
itors of DNA topoisomerase II (see p. 240), the substrate of this enzyme (a peptide with
known as gyrase inhibitors (center), restrict the C-terminal sequence D-Ala–D–Ala) and is
replication and thus bacterial reproduction. therefore reversibly bound in the active cen-
A large group of antibiotics attack bacterial ter. This brings the β–lactam ring into prox-
ribosomes. These inhibitors of translation imity with an essential serine residue of the
(left) include the tetracyclines—broad-spec- enzyme. Nucleophilic substitution then re-
trum antibiotics that are effective against a sults in the formation of a stable covalent
large number of different pathogens. The ami- bond between the enzyme and the inhibitor,
noglycosides,ofwhich streptomycin is the blocking theactivecenter (seep. 96).In divid-
best-known, affect all phases of translation. ing bacteria, the loss of activity of the enzyme
Erythromycin impairs the normal functioning leads to the formation of unstable cell walls
of the large ribosomal subunit. Chlorampheni- and eventually death.
col, one of the few natural nitro compounds,
inhibits ribosomal peptidyltransferase. Fi-
nally, puromycin mimics an aminoacyl tRNA
and therefore leads to premature interruption
of elongation.
The E–lactam antibiotics (bottom right) are
also frequently used. The members of this
group, the penicillins and cephalosporins, are

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