Acetyltransferases, inactivation

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. 

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... 

Plasmid- ortransposon-encoded chloramphenicol acetyltransferases (CATs) are responsible for resistance by inactivating the antibiotic. CATs convert chloramphenicol to an acetoxy derivative which fails to bind to the ribosomal target. Several CATs have been characterized and found to differ in properties such as elecfrophorefic mobilify and cafalyfic acfivify. 

Similarly, polymorphisms on the A -acetyltransferase 1 and 2 genes (NATl, NAT2) that encode the enzymes responsible for inactivating 5-aminosalicylate and sulfapyridine did not influence response to therapy or toxicity (46). 

Figure 8.16 Chromomycin derivatives generated by inactivating methyltransferase and acetyltransferase genes.

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. 

Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. , , and , acetyltransferase , phosphotransferase , adenylyltransferase. Amikacin is resistant to modification at , , , and . 

Polyamines like spermidine and spermine, which bind tightly to nucleic acids and are abundant in rapidly proliferating cells, are present in parasitic helminths in amounts comparable to those in vertebrate cells. As the enzymes necessary for their synthesis are lacking in adult parasitic flatworms, it is assumed that these compounds are obtained from the host (Bacchi and Yarlett, 1 995). In F. hepatica a polyamine N-acetyltransferase has been characterized, that is thought to play a major role in the polyamine metabolism of this parasite by inactivating excess amines (Aisien and Walter, 1993). 

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. 

Resistance can be caused by 1) decreased uptake of drug when the oxygen-dependent transport system for aminoglycosides is absent an altered receptor where the 30S ribosomal subunit binding site has a lowered affinity for aminoglycosides plasmid-associated synthesis of enzymes (for example, acetyltransferases, nucleotidyltransferases, and phosphotransferases) that modify and inactivate aminoglycoside... 

Enzymatic detoxification or modification AGAC antibiotics /(-Lactams Chloramphenicol Erythromycin Tetracyclines Mercury compounds Formaldehyde Modification by acetyltransferases, adenylylases or phosphotransferases Inactivation (/(-lactamases) Inactivation (acetyltransferases) Esterases produce anhydroerythromycin Enzymatic inactivation Inactivation (hydrolases, lyases) Dehydrogenase... 

The lincosamides, lincomycin and clindamycin are active against Grampositive bacteria. Plasmid-mediated inactivation from enzymatic nucleo-tidylation occurs in some staphylococci. Plasmid-encoded enzymes can modify streptogramin A (O-acetyltransferase enzyme) and streptogramin B (hydrolase enzyme involved) in S. aureus [198, 199], There is no evidence that bacteria can circumvent the action of other antibiotics for example, mupirocin is not degraded [200]. 

N-Acetyltransferase uses acetyl-CoA to acetylate the amino moiety of arylal-kylamines. In mammalian pineal gland, this enzyme catalyzes the production of N-acetyl-5-hydroxytryptamine, which is the precursor of melatonin. It is also involved in the inactivation of monoaminergic neurotransmitters in insects. 

Acetyl CoA acetyltransferase, a key enzyme of ketogenesis, and 3-oxo-acyl CoA thiolase, involved in -oxidation, bind CoA by formation of a disulfide bond to cysteine, a reaction that can be reversed by glutathione and other sulfhydryl reagents. The physiological significance of this reaction with CoA, which inactivates the enzymes, is not clear (Quandt and Huth, 1984, 1985 Schwerdt and Huth, 1993). 

Sugantino M, Roderick SL. Crystal structure of Vat(D) an acetyltransferase that inactivates streptogramin group A antibiotics. Biochemistry 2002 41 2209-2216. 

Chase JFA, Tubbs PK. Conditions for self-catalysed inactivation of carnitine acetyltransferase-a novel form of enzyme inhibition. Biochem. J. 1969 111 225-235. 

Acetylation. Although modified by kanamycin acetyltransferase (Figure 7.10), complete inactivation of neomycin does not take place [46]. Thus, the acetylating enzyme plays no significant role in the resistance of Ps. aeruginosa to neomycin. 

Gentamicin is also a substrate for the enzyme kanamycin acetyltrans-ferase but is not inactivated by it. However, 6-N-acetylgentamicin Cia, the acylation product of gentamicin C,a by kanamycin acetyltransferase, can be acetylated by gentamicin acetyltransferase I. The resulting diacetate of gentamicin C,a is inactive as an antibiotic [46]. 

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