Chloramphenicol

Chloramphenicol (chloromycetin) (Figure 4.14) was initially isolated from cultures of Streptomyces venezuelae, but is now obtained for drug use by chemical synthesis. It was one of the first broad spectrum antibiotics to be developed, and exerts its antibacterial action by inhibiting protein biosynthesis. It binds reversibly to the 50S subunit of the bacterial ribosome, and in so doing disrupts peptidyl transferase, the enzyme that catalyses peptide bond formation (see page 408). This reversible binding means that bacterial cells not destroyed may resume protein biosynthesis when no longer exposed to the antibiotic. Some microorganisms have developed resistance to chloramphenicol by an inactivation process involving enzymic acetylation of the primary alcohol group in the antibiotic. The acetate binds only very weakly to the ribosomes, so has little antibiotic activity. The value of chloramphenicol as an antibacterial agent has been severely limited by some serious side-effects. It can cause blood disorders including irreversible aplastic anaemia in certain individuals, and these can lead to leukaemia and perhaps prove fatal. Nevertheless, it is still the drug of choice for some life-threatening infections such as typhoid fever and bacterial meningitis. The blood constitution must be monitored regularly during treatment to detect any abnormalities or adverse changes. The drug is orally active, but may also be injected. Eye-drops are useful for the treatment of bacterial conjunctivitis.

decarboxylation and aromatization; amino group is retained via an additional oxidation step (amine ^ imine)

CO2H O

"O co2h nh2

4-amino-4-deoxy-chorismic acid

Figure 4.14

hydroxylation CO2H N-acylation

NHCOCHCl2 CHCl2COSCoA

NO2 chloramphenicol

transamination

CO2H NH2

L-p-aminophenylalanine L-PAPA

Figure 4.14

E2 elimination co2h ofammonia co2h

'nh2

cinnamic acid hydroxylation co2h rNH2 ? -

L-Tyr sequence of hydroxylation and methylation reactions hydroxylation sequence of hydroxylation and methylation reactions

4-coumaric acid (p-coumaric acid)

caffeic acid

ferulic acid

4-coumaric acid (p-coumaric acid)

ch2oh

caffeic acid

ferulic acid

4-hydroxycinnamyl alcohol (p-coumaryl alcohol)

ch2oh

coniferyl alcohol

OH MeO y OMe OH OH

sinapic acid

CH2OH

CH2OH

MeO y OMe OH

MeO y OMe OH

sinapyl alcohol x V

LIGNANS

NADPH

POLYMERS

LIGNIN

CO2H

chlorogenic acid (5-O-caffeoylquinic acid)

HO HO

chlorogenic acid (5-O-caffeoylquinic acid)

HO HO

1- O-cinnamoylglucose

1- O-cinnamoylglucose

sinapine

Figure 4.16

sinapine

Figure 4.16

capable of deaminating tyrosine, is still debated. Those species that do not transform tyrosine synthesize 4-coumaric acid by direct hydroxylation of cinnamic acid, in a cytochrome P-450-dependent reaction, and tyrosine is often channelled instead into other secondary metabolites, e.g. alkaloids. Other cinnamic acids are obtained by further hydroxylation and methylation reactions, sequentially building up substitution patterns typical of shikimate pathway metabolites, i.e. an ortho oxygenation pattern (see page 123). Some of the more common natural cinnamic acids are 4-coumaric, caffeic, ferulic, and sinapic acids (Figure 4.15). These can be found in plants in free form and in a range of esterified forms, e.g. with quinic acid as in chlorogenic acid (5-O-caffeoylquinic acid) (see coffee, page 395), with glucose as in 1-O-cinnamoylglucose, and with choline as in sinapine (Figure 4.16).

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