Chloramphenicol acetyltransferase inactivating enzymes

Although Table 20.7 lists only benzylpenicillin and ampicillin as being inactivated by p-lactamase (from B. cereus), other P-lactams may also be hydrolysed by P-lactamases. Other antibioticinactivating enzymes are also known (Chapter 13) and have been considered as possible inactivating agents, e.g. chloramphenicol acetyltransferase (inactivates chloramphenicol) and enzymes that modify aminoglycoside antibiotics. 

Chloramphenicol is able to inhibit the peptidyl transferase reaction and so bacterial protein synthesis by binding reversibly to the 50s ribosomal subunit. Resistance can occur due to the plasmid-mediated enzyme chloramphenicol acetyltransferase which inactivates the drug by acetylation. Such resistance is often a part of plasmid-mediated multidrug resistance. Resistance can also occur by an altered bacterial permeability. However in most instances resistance to chloramphenicol only develops slowly and remains partial. 

Low-level resistance to chloramphenicol may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug. 

Chloramphenicol is a bacteriostatic agent that binds to the 508 ribosomal subunit and inhibits the transpeptidation in protein synthesis. While this agent is not widely used to treat staphylococcal infection, resistance to chloramphenicol is due to inactivation of the antibiotic by chloramphenicol acetyltransferase enzyme (CA7). Macrolides, such as erythromycin and oleandomycin lincosamides, such as lincomycin and clindamycin and streptogramin antibiotics also have a bacteriostatic effect on Staphylococcus spp. by binding to their 508 ribosomal subunit, arresting protein synthesis, but resistance to these antibiotics is also prevalent. Rifampin has also been used to treat staphylococcal infections, but when used alone, resistant strains quickly arise. 

A chloramphenicol-resistant gj aureus as well as enteric bacteria carrying R-factor inactivate the antibio-tic 2 2 through conversion to the 3-0-acetyl- or 1,3-0,0-diacetyl derivative by chloramphenicol-acetyltransferase with utilization of acetyl-CoA. The 3-deoxy analog of chloramphenicol, which is itself neither an effective antibiotic nor a substrate for the transferase, was found to be a potent inducer of the enzyme. 

As discussed earlier in this chapter, one of the few indications still left for the application of chloramphenicol is the treatment of severe infections caused by H. influenzae which has been shown to be resistant to ampicillin, or is expected to be so. Recently, resistance to chloramphenicol has been encountered in H. influenzae. It was shown that the strain produced an enzyme, presumably acetyltransferase, inactivating both chloramphenicol and thiamphenicol. The... 

Enzymic inactivation The ability to destroy or inactivate the antimicrobial agent also can confer resistance on microorganisms. For example, (3-lactamases destroy many penicillins and cephalosporins and an acetyltransferase can convert chloramphenicol to an inactive compound. 

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