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PHL 424
Antimicrobials
1st Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Inhibitors of bacterial protein synthesis,
Overview
 These agents are bacteriostatic, protein-synthesis inhibitors that target the
ribosome
 Examples: Chloramphenicol, macrolides, clindamycin, tetracyclines
 Reason For Selective Toxicity
 These antibiotics exert their antimicrobial effects by targeting the bacterial
ribosome, which has components that differ structurally from those of the
mammalian cytoplasmic ribosome
 In general, the bacterial ribosome is smaller (70S) than the mammalian
ribosome (80S)
 Bacterial ribosome is composed of 50S and 30S subunits, whereas human
ribosome is comprised of 60S and 40S subunits
Inhibitors of bacterial protein synthesis,
General MOA
Chloramphenicol
Tetracyclines
Θ
Θ
(P-site)
(A-site)
Θ
Macrolides,
clindamycin
Inhibitors of bacterial protein synthesis,
Chloramphenicol
 It is an antibiotic produced by Streptomyces
venezuelae
 It is a potent inhibitor of microbial protein synthesis
 MOA: It binds reversibly to the 50S subunit of the bacterial ribosome and thus
inhibits the peptidyl transferase step of protein synthesis {i.e., it inhibits the
transpeptidation reaction (1)} ……How?
 It binds to the 50S ribosomal subunit at the peptidyltransferase site, thus the
interaction between peptidyltransferase and its amino acid substrate cannot occur,
and peptide bond formation is inhibited
 It also can inhibit mammalian mitochondrial protein synthesis {mitochondrial
ribosomes resemble bacterial ribosomes (both are 70S)}
 The peptidyltransferase of mammalian mitochondrial ribosomes, but not of
cytoplasmic ribosomes, is inhibited by chloramphenicol  inhibition of
synthesis of proteins of the inner mitochondrial membrane
 Mammalian erythropoietic cells are particularly sensitive to the drug
 Much of the toxicity observed with this drug can be attributed to these effects
Inhibitors of bacterial protein synthesis,
Chloramphenicol, contd.
 Antimicrobial Actions:
 It is a bacteriostatic broad-spectrum antibiotic that is active against both
aerobic and anaerobic G+ve and G-ve organisms
 It is active also against rickettsiae and mycoplasma
 Haemophilus influenzae, Neisseria meningitidis and Bordetella pertussis
are highly susceptible
 Strains of S. aureus tend to be less susceptible
 P. aeruginosa is resistant to even very high concentrations of the drug
 Resistance:
 It is usually caused by a plasmid-encoded acetyltransferase that inactivates
the drug. Acetylated derivatives of chloramphenicol fail to bind to bacterial
ribosomes
 Resistance also can result from decreased permeability and from
ribosomal mutation
Inhibitors of bacterial protein synthesis,
Chloramphenicol, contd.
 Pharmacokinetics
 It is readily absorbed from the GIT
 The parenteral formulation, chloramphenicol succinate, yields free
chloramphenicol by hydrolysis, giving blood levels lower than those
achieved with orally administered drug
 After absorption, it is widely distributed in body fluids and readily reaches
therapeutic concentrations in CSF
 Hepatic metabolism to the inactive glucuronide is the major route of
elimination. This metabolite and chloramphenicol itself are excreted in the
urine. About 50% of chloramphenicol is bound to plasma proteins; such
binding is reduced in cirrhotic patients and in neonates
 Patients with cirrhosis or otherwise impaired hepatic function have
decreased metabolic clearance, and dosage should be adjusted in these
individuals
Inhibitors of bacterial protein synthesis,
Chloramphenicol, contd.
 Therapeutic Uses:
 Because of potential toxicity, bacterial resistance, and the availability of other
effective drugs (e.g., cephalosporins), chloramphenicol is almost an obsolete as
a systemic drug
 It may be considered for treatment of serious rickettsial infections in children for
whom tetracyclines are contraindicated, i.e., those under 8 years of age
 It is an alternative to b-lactam antibiotics for treatment of meningococcal
meningitis occurring in patients who have major hypersensitivity reactions to
penicillin or bacterial meningitis caused by penicillin-resistant strains of
pneumococci
 It is used topically in the treatment of eye infections because of its wide
antibacterial spectrum and its penetration of ocular tissues and the aqueous
humor
Inhibitors of bacterial protein synthesis,
Chloramphenicol, contd.
 Side effects:
 The most important adverse effect of chloramphenicol is on the bone marrow
It affects the hematopoietic system in two ways: a dose-related toxicity that
presents as anemia, leukopenia, or thrombocytopenia; and an idiosyncratic
response manifested by aplastic anemia, leading in many cases to fatal
pancytopenia
A genetic predisposition is suggested by the occurrence of pancytopenia in
identical twins
Aplastic anemia accounts for approximately 70% of cases of blood dyscrasias
due to chloramphenicol, while hypoplastic anemia, agranulocytosis, and
thrombocytopenia make up the remainder
 Dose-related, reversible erythroid suppression due to an inhibitory action of
chloramphenicol on mitochondrial protein synthesis in erythroid precursors,
which in turn impairs iron incorporation into heme
 Nausea and vomiting, unpleasant taste, diarrhea, and perineal irritation may
follow the oral administration of chloramphenicol
 Oral or vaginal candidiasis may occur as a result of alteration of normal
microbial flora
Inhibitors of bacterial protein synthesis,
Chloramphenicol, contd.
 Side effects, cont.d
 Toxicity for Newborn Infants
Newborn infants, especially if premature, lack an effective glucuronic acid
conjugation mechanism for the degradation & detoxification of chloramphenicol,
with subsequent inadequate renal excretion of unconjugated drug
Consequently, when infants are given dosages above 50 mg/kg/d, the drug may
accumulate, resulting in a serious illness termed gray baby syndrome, with
vomiting, refusal to suck, passage of loose, green stools, cyanosis, ashen-gray
color, flaccidity, hypothermia, shock and collapse
Death occurs in about 40% of patients within 2 days of initial symptoms. Those
who recover usually exhibit no sequelae
 To avoid this toxic effect, chloramphenicol should be used with caution in infants,
and the dosage limited to 50 mg/kg/d or less (during the first week of life) in fullterm infants and 25 mg/kg/d in premature infants
 Toxic effects have not been observed in the newborns when as much as 1 g of
the antibiotic has been given every 2 hours to the mothers during labor
Inhibitors of bacterial protein synthesis,
Chloramphenicol, contd.
 Drug interactions:
 It inhibits hepatic microsomal enzymes that metabolize several drugs such as
warfarin
 Conversely, other drugs may alter the drug elimination. Concurrent
administration of phenobarbital or rifampin, which potently induce CYPs,
shortens its t1/2 and may result in subtherapeutic drug concentrations
 Like other bacteriostatic inhibitors of microbial protein synthesis,
chloramphenicol can antagonize bactericidal drugs such as penicillins or
aminoglycosides