Resistance to Chloramphenicol

Chloramphenicol, streptomycin and kanamycin are all antibiotics that inhibit protein synthesis by binding to the bacterial ribosomes. The difference in mechanism between resistance due to chromosomal mutations as opposed to plasmid-borne genes is espe-

bla gene Gene encoding \-lactamase thereby providing resistance to ampicillin. Same as amp gene clavulanic acid And its derivatives bind to \-lactamases and react forming a covalent bond to the protein that kills the enzyme

FIGURE 16.13 Inactivation of Chloramphenicol

The side chain of chloramphenicol has two -OH groups that are important for binding to the bacterial ribosomes. Chloramphenicol acetyl transferase, produced by R-plasmids, catalyzes the addition of two acetyl groups to chloramphenicol. The enzyme uses acetyl-CoA as a source for the acetyl groups. The resulting 1,3-diacetyl-chloramphenicol can no longer bind to the ribosomes.

FIGURE 16.13 Inactivation of Chloramphenicol

The side chain of chloramphenicol has two -OH groups that are important for binding to the bacterial ribosomes. Chloramphenicol acetyl transferase, produced by R-plasmids, catalyzes the addition of two acetyl groups to chloramphenicol. The enzyme uses acetyl-CoA as a source for the acetyl groups. The resulting 1,3-diacetyl-chloramphenicol can no longer bind to the ribosomes.

Chloramphenicol is inactivated by addition of acetyl groups.

dally notable for these antibiotics. Chromosomal mutants usually have altered ribosomes that no longer bind the antibiotic. Not surprisingly such mutations often cause slower or less accurate protein synthesis and the cells grow poorly. In contrast, plasmid-borne resistance to these antibiotics usually involves chemical attack on the antibiotic itself by specific enzymes encoded by the plasmid.

Chloramphenicol binds to the 23S rRNA of the large subunit of the bacterial ribo-some and inhibits the peptidyl transferase reaction (see Ch. 8). R plasmids protect the bacteria by producing the enzyme, chloramphenicol acetyl transferase (CAT). CAT transfers two acetyl groups from acetyl CoA to the side chain of chloramphenicol. This prevents binding of the antibiotic to the 23S rRNA (Fig. 16.13). Replacement of the terminal -OH of chloramphenicol with fluorine results in non-modifiable yet still antibacterially active derivatives. There are two major groups of chloramphenicol acetyl transferase, one from gram-positive and one from gram-negative bacteria. The two groups differ greatly from each other except for the chloramphenicol-binding region.

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