- Bacterial nucleic acid synthesis
Sulfonamides (bacteriostatic; inhibit bacterial folic acid synthesis)
Trimethoprim (bacteriostatic; inhibits bacterial folic acid synthesis)
Quinolones (bacteriostatic; inhibit DNA gyrase)
e.g., ciprofloxacin, cinoxacin, enoxacin, norfloxacin
Rifampin (bactericidal; blocks mRNA synthesis in bacteria, inhibits RNA
polymerase)
Table 9.2 lists various bacteria and their susceptibility to different classes of antibacterial
agents.
9.4.1 Antibacterials Targeting Cell Wall SynthesisThe successful chemotherapeutic management of any host–parasite interaction—whether
viral, bacterial, or protozoan—depends upon the exploitation of biochemical differences
between the host and the parasite. The greater these differences are, the better the likeli-
hood of finding or designing drugs that exploit them and inhibit some crucial function of
the parasite in order to kill it without harming the host cell. This almost utopian goal (Paul
Ehrlich’s “magic bullet”) has been approximated very closely in the case of cell wall syn-
thesis inhibitors, such as antibacterial agents, for the simple reason that a very funda-
mental difference exists between bacteria and mammalian cells: the former have cell walls
and the latter do not. The rigid cell wall of bacteria encloses and strengthens the vulnera-
ble cell membrane, which is subjected to considerable internal osmotic pressure. If the
integrity of the cell wall is impaired, the bacterial cell will undergo breakdown (lysis) and
the bacterium will perish. The antibiotics that inhibit cell wall synthesis cannot find an
analogous target in animal cells and are in most cases extremely nontoxic.
Cell walls are complex and variable structures but have a number of common char-
acteristics, discussed in most biochemistry textbooks and numerous monographs. The
basic structural unit of the wall is the muropeptide [murus(Latin)=wall], a repeating
disaccharide linked through a lactyl ether to a tetrapeptide. The peptides are, in turn,
crosslinked (in Staphylococcus aureus) by a pentaglycine chain. The resulting polymer,
calledmurein,forms a closed sack around the bacterium and can be dissolved by the
enzyme lysozyme. Other glycopeptides, such as teichoic acid, and polypeptides con-
tribute to the antigenic properties of bacteria.
The classical division of bacteria into Gram-positive and Gram-negative groups on the
basis of specific staining procedures also depends on cell wall components. The Gram-
positive organisms have a rigid cell wall that is covered with an outer layer containing
teichoic acids, whereas the wall of Gram-negative bacteria is covered with a smooth,
soft lipopolysaccharide. Most penicillins are much more effective against Gram-positive
bacteria.
During the biosynthesis of the cell wall, the muropeptide is formed from acetylmuramyl-
pentapeptide, which terminates in a D-alanyl-D-alanine. The synthesis of this precur-
sor is inhibited by the antibiotic cycloserine (9.36), a compound produced by many
Streptomyces fungi but which is not used clinically. During the crosslinking of the pen-
tapeptide precursor, the terminal fifth alanine must be split off by a transpeptidase
enzyme. This last reaction in cell wall synthesis is inhibited by the β-lactam antibiotics,
562 MEDICINAL CHEMISTRY