ANTIBACTERIAL

AGENTS

Bonniface Obura, BPharm, MSc.

 Outline

• Protein Synthesis inhibitors,

• Nucleic acid inhibitors

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 Protein synthesis inhibitors

• Protein synthesis takes place on ribosomes.

• Eukaryotic and prokaryotic ribosomes differ; basis for selectivity

• Bacterial ribosome consists of 50S and 30S subunits whereas

mammalian ribosome has 60S and 40S subunits

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Protein synthesis inhibitors
Mechanisms of Inhibition

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Protein synthesis inhibitors
Mechanisms of Inhibition

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 TETRACYCLINES

✓ The tetracyclines are broad-spectrum antibiotics.

✓ The group includes :
• tetracycline,
• oxytetracycline,
• demeclocycline,
• lymecycline,
• doxycycline,
• minocycline
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• tigecycline.
 Tetracyclines Cont..

✓ Prototype; Chlortetracycline, introduced in 1948, but is no longer in use.

✓ Tetracyclines are "broad-spectrum" antibiotics act against:
• Rickettsia, gram-positive
• gram-negative bacteria,
• aerobes,
• anaerobes,
• and Chlamydia.
✓ They are sufficiently similar to permit discussion as a group
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Tetracyclines Cont..

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 Tetracyclines Cont..
Sources

✓ Oxytetracycline is a natural product elaborated by Streptomyces

rimosus.

✓ Tetracycline is a semisynthetic derivative of chlortetracycline.

✓ Demeclocycline is the product of a mutant strain of Strep. aureofaciens,

and methacycline,

✓ doxycycline, and minocycline all are semisynthetic derivatives.

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Tetracyclines Cont..
Mechanism of action

✓ Tetracyclines are taken up into susceptible

organisms by active transport

✓ Inhibit bacterial protein synthesis by binding

to the 30S subunit and blocking tRNA binding
to the A site.

✓ They are bacteriostatic

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 Tetracyclines Cont..
Pharmacokinetics

✓ Absorption:

• Minocycline and doxycycline are well absorbed orally.

• The absorption of most other tetracyclines is irregular and incomplete but
is improved in the absence of food.

• Tetracyclines chelate metal ions (calcium, magnesium, iron, aluminium),

forming non-absorbable complexes,

• Absorption is decreased in the presence of milk, certain antacids and iron

preparations. 11
 Tetracyclines Cont..
Pharmacokinetics

✓ Distribution:

• widely throughout the body and into tissues and secretions, including urine
and prostate.

• accumulate in reticuloendothelial cells of the liver, spleen, and bone

marrow, and in bone, dentine, and enamel of unerupted teeth

• Tetracyclines cross the placenta and enter the fetal circulation and
amniotic fluid.

• Relatively high concentrations of these drugs also are found in breast milk. 12
 Tetracyclines Cont..
Pharmacokinetics

✓ Excretion:

• Primary route of elimination for most tetracyclines is the kidney

• After biliary excretion, tetracyclines are partially reabsorbed via
enterohepatic recirculation.

• Minocycline is an exception and is significantly metabolized by the liver.

• Doxycycline at recommended doses does not accumulate significantly in
patients with renal failure. The drug is excreted in the feces. .
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 Tetracyclines Cont..
Therapeutic uses

✓ Used extensively to treat infectious diseases

✓ Additive to animal feeds to facilitate growth.
✓ Extensive use has led to increased bacterial resistance, but the drugs
remain useful for infections caused by:
• Rickettsia,
• Mycoplasmas,
• Chlamydiae.

✓ Doxycycline is useful for treatment of respiratory tract infections

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 Tetracyclines Cont..
Adverse effects

✓ Gastrointestinal disturbances
✓ Stain and sometimes cause dental hypoplasia and bone deformities.
✓ Hepatotoxicity in pregnant women.
✓ Phototoxicity with demeclocycline.
✓ Minocycline can produce vestibular disturbances
✓ High doses of tetracyclines can decrease protein synthesis in host cells,
an antianabolic effect that may result in renal damage.
✓ Long-term therapy can cause disturbances of the bone marrow 15
 CHLORAMPHENICOL

• Chloramphenicol is produced by Streptomyces venezuelae, was

introduced into clinical practice in 1948.

• With the drug's wide use, it became evident that chloramphenicol could
cause serious and fatal blood dyscrasias.

• Currently is reserved for treatment of life-threatening infections (e.g.,

meningitis, rickettsial infections) in patients who cannot take safer
alternatives because of resistance or allergies

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Chloramphenicol Cont..
Mechanism of action

• Bind reversibly to the 50S

ribosomal subunit
• Inhibits transpeptidation;
interaction between
peptidyltransferase and its amino
acid substrate cannot occur.
• Chloramphenicol also can inhibit
mitochondrial protein synthesis in
mammalian cells
• Mammalian erythropoietic cells are
particularly sensitive to the drug.
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 Chloramphenicol Cont..
Pharmacokinetics

✓ Absorbed rapidly from the GIT; peak concentrations of 10 to 13 mg/ml

occur within 2 to 3 hours after the administration of a 1-g dose.

✓ The preparation of chloramphenicol for parenteral use is a water-

soluble, inactive prodrug sodium succinate.

✓ Hydrolysis of chloramphenicol succinate by esterases occurs in vivo.

✓ Chloramphenicol succinate is rapidly cleared from plasma by the

kidneys
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 Chloramphenicol Cont..
Pharmacokinetics

✓ Chloramphenicol is widely distributed in body fluids and readily reaches

therapeutic concentrations in CSF

✓ Chloramphenicol is present in bile, milk, and placental fluid.

✓ It is also found in the aqueous humor after subconjunctival injection

✓ Hepatic metabolism to the inactive glucuronide is the major route of

elimination

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 Chloramphenicol Cont..
Therapeutic uses

✓ Limited to infections for which the benefits of the drug outweigh the
risks of the potential toxicities

✓ Typhoid Fever: many strains of Salmonella typhi are often sensitive

✓ Bacterial Meningitis: alternative drug for the treatment of meningitis

caused by H. influenzae, N. meningitidis, and S. pneumoniae

✓ Anaerobic Infections: quite effective against most anaerobic bacteria

✓ Rickettsial Diseases: in patients allergic to tetracyclines

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 Chloramphenicol Cont..
Adverse effects

✓ Inhibits the synthesis of proteins of the inner mitochondrial membrane,

probably by inhibiting the ribosomal peptidyltransferase
✓ Much of the toxicity observed can be attributed to:
• Hypersensitivity Reactions
• Hematological Toxicity
• Neonates may develop gray baby syndrome (a developmental
deficiency of glucuronyl transferase or inadequate renal excretion
of unconjugated drug)
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 MACROLIDES

• Examples; erythromycin, azithromycin, clarithromycin

• Erythromycin was discovered in 1952 as a metabolic product of a strain

of Streptomyces erythreus.

• Clarithromycin and azithromycin are semisynthetic derivatives of

erythromycin

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 Macrolides Cont..
Antibacterial activity

✓ Erythromycin usually is bacteriostatic, but may be bactericidal in high concentrations

against susceptible organisms.
✓ Erythromycin is inactive against most aerobic enteric gram-negative bacilli.
✓ Clarithromycin is slightly more potent than erythromycin against sensitive strains of
streptococci and staphylococci, and has modest activity against H. influenzae and N.
gonorrhoeae.
✓ Azithromycin generally is less active than erythromycin against gram-positive organisms
and slightly more active than either erythromycin or clarithromycin against H. influenzae
and Campylobacter spp
✓ Macrolide resistance is common among streptococci. cross-resistance is complete
among macrolides. 23
Macrolides Cont..
Mechanism of action

✓ Inhibit protein synthesis by binding

reversibly to the 50S ribosomal
subunits
✓ Alternatively, macrolides may bind and
cause a conformational change that
terminates protein synthesis by
indirectly interfering with
transpeptidation and translocation.

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 Macrolides Cont..
Mechanisms of resistance

✓ drug efflux by an active pump mechanism (encoded by mrsA, mefA, or

mefE in staphylococci, group A streptococci, or S. pneumoniae,
respectively)
✓ ribosomal protection by inducible or constitutive production of
methylase enzymes, mediated by expression of ermA, ermB, and ermC,
which modify the ribosomal target and decrease drug binding
✓ macrolide hydrolysis by esterases produced by Enterobacteriaceae
✓ chromosomal mutations that alter a 50S ribosomal protein (found in B.
subtilis, Campylobacter spp., mycobacteria, and gram-positive cocci). 25
Macrolides Cont..
Pharmacokinetics

✓ Absorption:
▻ Erythromycin base is incompletely but adequately absorbed.
▻ Because it is inactivated by gastric acid, the drug is administered as enteric-
coated tablets, as capsules containing enteric-coated pellets that dissolve in the
duodenum, or as an ester.
▻ Food, which increases gastric acidity, may delay absorption.
▻ Clarithromycin is absorbed rapidly from the gastrointestinal tract after oral
administration, but first-pass metabolism reduces its bioavailability to 50% to 55%.
▻ Azithromycin administered orally is absorbed rapidly and distributes widely
throughout the body, except to the brain and
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Macrolides Cont..
Pharmacokinetics

✓ Distribution:
▻ Erythromycin diffuses readily into intracellular fluids, achieving antibacterial
activity in essentially all sites except the brain and CSF
▻ Clarithromycin and its active metabolite, 14-hydroxyclarithromycin, distribute
widely and achieve high intracellular concentrations throughout the body
▻ Azithromycin's unique pharmacokinetic properties include extensive tissue
distribution and high drug concentrations within cells (including phagocytes),
resulting in much greater concentrations of drugs in tissue or secretions
compared to simultaneous serum concentrations

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 Macrolides Cont..
Pharmacokinetics

✓ Elimination:
▻ Only 2% to 5% of orally administered erythromycin is excreted in active
form in the urine; this value is from 12% to 15% after intravenous infusion
▻ Clarithromycin is eliminated by renal and nonrenal mechanisms. It is
metabolized in the liver to several metabolites, the active 14-hydroxy
metabolite being the most significant
▻ Azithromycin undergoes some hepatic metabolism to inactive
metabolites, but biliary excretion is the major route of elimination

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Macrolides Cont..
Therapeutic uses
✓ Mycoplasma pneumoniae Infections
✓ Legionnaires' Disease
✓ Chlamydial Infections
✓ Diphtheria
✓ Pertussis
✓ Streptococcal Infections
✓ Staphylococcal Infections
✓ Campylobacter Infections
✓ Helicobacter pylori Infection
✓ Tetanus.
✓ Syphilis
✓ Mycobacterial Infections
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 AMINOGLYCOSIDES

• Examples; gentamicin, tobramycin, amikacin, netilmicin, kanamycin,

streptomycin, and neomycin
• Primarily used to treat infections caused by aerobic gram-negative bacteria;
streptomycin is an important agent for the treatment of tuberculosis
• Bactericidal inhibitors of protein synthesis; concentration-dependent
• Sources; natural or semisynthetic derivatives of compounds produced by a
variety of soil actinomycetes
• Streptomycin was first isolated from a strain of Streptomyces griseus.
• Gentamicin and netilmicin derived from actinomycete Micromonospora 30
Aminoglycosides Cont..
Mechanism of action

Interfere with protein synthesis by causing misreading and premature termination of mRNA translation
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 Aminoglycosides Cont..
Mechanisms of resistance

✓ failure of the antibiotic to penetrate intracellularly,

✓ low affinity of the drug for the bacterial ribosome,
✓ inactivation of the drug by microbial enzymes
✓ Amikacin is a suitable substrate for only a few of these inactivating
enzymes
✓ Resistance to gentamicin indicates cross-resistance to tobramycin,
amikacin, kanamycin, and netilmicin because the inactivating enzyme is
bifunctional and can modify all these aminoglycosides
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 Aminoglycosides Cont..
Antibacterial activity

✓ Gentamicin, tobramycin, kanamycin, netilmicin, and amikacin are

against aerobic gram-negative bacilli.
✓ Kanamycin, like streptomycin, has a more limited spectrum compared
with other aminoglycosides (not be used to treat infections caused by
Serratia or P. aeruginosa)
✓ In combination with a cell wall-active agent, such as a penicillin or
vancomycin, an aminoglycoside (streptomycin and gentamicin)
produces a synergistic bactericidal effect in vitro against enterococci,
streptococci, and staphylococci.
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 Aminoglycosides Cont..
Pharmacokinetics

✓ Aminoglycosides are highly polar cations and therefore are very poorly absorbed from the
gastrointestinal tract
✓ All aminoglycosides are absorbed rapidly from intramuscular sites of injection
✓ Aminoglycosides do not penetrate into most cells, the central nervous system (CNS), and
the eye
✓ Except for streptomycin, there is negligible binding of aminoglycosides to plasma albumin
✓ Aminoglycosides are excreted almost entirely by glomerular filtration, and urine
concentrations of 50 to 200 mg/ml are achieved
✓ The half-lives of the aminoglycosides in plasma are similar and vary between 2 and 3
hours in patients with normal renal function
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 Aminoglycosides Cont..
Adverse effects

✓ Ototoxicity. Vestibular and auditory dysfunction can follow the

administration of any of the aminoglycosides
✓ Nephrotoxicity. Approximately 8% to 26% of patients who receive an
aminoglycoside for more than several days will develop mild renal
impairment that is almost always reversible
✓ Neuromuscular Blockade

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 CLINDAMYCIN

• Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes and

suppresses protein synthesis.
• Although clindamycin, erythromycin, and chloramphenicol are not structurally
related, they act at sites in close proximity
• Clindamycin generally is similar to erythromycin in its in vitro activity against
susceptible strains of pneumococci, S. pyogenes, and viridans streptococci.
• Clindamycin is more active than erythromycin or clarithromycin against
anaerobic bacteria

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 Clindamycin Cont..

• Clindamycin is nearly completely absorbed following oral administration

• Clindamycin is widely distributed in many fluids and tissues, including bone
• Only about 10% of the clindamycin administered is excreted unaltered in the
urine, and small quantities are found in the feces

• Clindamycin is inactivated by metabolism to N-demethylclindamycin and

clindamycin sulfoxide, which are excreted in the urine and bile

• Incidence of diarrhea associated with the administration of clindamycin ranges

are reported to be from 2% to 20% 37
 QUINUPRISTIN/DALFOPRISTIN

• Quinupristin/dalfopristin is active against gram-positive cocci, including S.

pneumoniae, beta- and alpha-hemolytic strains of streptococci, E. faecium

• Quinupristin and dalfopristin are protein synthesis inhibitors that bind the 50S
ribosomal subunit

• Quinupristin/dalfopristin is administered only by intravenous infusion

over at least 1 hour
• Hepatic metabolism by conjugation is the principal means of clearance
for both compounds, with 80% of an administered dose eliminated by
biliary excretion 38
 Quinupristin/Dalfopristin Cont..

• Approved in the US for treatment of infections caused by vancomycin-resistant

strains of E. faecium and complicated skin and skin-structure infections caused
by methicillin-susceptible strains of S. aureus or S. pyogenes

• The most common side effects are infusion-related events, such as pain and
phlebitis

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 LINEZOLID

• Synthetic antimicrobial agent of the oxazolidinone class

• Active against gram-positive organisms including staphylococci, streptococci,
enterococci, gram-positive anaerobic cocci, and gram-positive rods such as
Corynebacterium spp. and Listeria monocytogenes

• Linezolid inhibits protein synthesis by binding to the P site of the 50S ribosomal
subunit and preventing formation of the larger ribosomal-fMet-tRNA complex
that initiates protein synthesis

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 Linezolid Cont..

• Linezolid is well absorbed after oral administration

• Linezolid is broken down by nonenzymatic oxidation to aminoethoxyacetic acid and
hydroxyethyl glycine derivatives
• Ten percent of the administered dose appears as oxidation products in feces
• Approved for treatment of:
✓ infections caused by vancomycin-resistant E. faecium;
✓ nosocomial pneumonia caused by methicillin-susceptible and-resistant strains of S. aureus;
✓ community-acquired pneumonia caused by penicillin-susceptible strains of S. pneumoniae;
✓ complicated skin and skin-structure infections caused by streptococci and methicillin-
susceptible and -resistant strains of S. aureus;
✓ uncomplicated skin and skin-structure infections
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NUCLEIC ACID INHIBITORS

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Nucleic acid inhibitors cont..

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 SULFONAMIDES

✓ Sulfonamide is employed herein as a generic name for derivatives of para-aminobenzene

sulfonamide
✓ Examples; sulfadiazide, sulfamethoxazole, sulfanilamide, sulfacetamide
✓ wide range of antimicrobial activity against both gram-positive and gram-negative
bacteria
✓ Resistance to sulfonamides is increasingly a problem (by random mutation and selection
or by transfer of resistance by plasmids )
✓ Sulfonamides, structural analogs and competitive antagonists of para-aminobenzoic acid
(PABA), prevent normal bacterial utilization of PABA for the synthesis of folic acid
(pteroylglutamic acid).
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✓ Exert a synergistic effect when used with trimethoprim
 Sulfonamides cont..

✓ Absorbed rapidly from the gastrointestinal tract. Approximately 70% to

100% of an oral dose is absorbed
✓ Bound in varying degree to plasma proteins, particularly to albumin
✓ Distributed throughout all tissues of the body
✓ sulfadiazine and sulfisoxazole penetrate the cerebrospinal fluid
✓ pass readily through the placenta and reach the fetal circulation
✓ The major metabolic derivative is the N4-acetylated sulfonamide
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 Sulfonamides cont..

Therapeutic uses
✓ Urinary Tract Infections: longer a therapy of first choice due to
resistance
✓ Toxoplasmosis: pyrimethamine and sulfadiazine
✓ Burn infections
✓ Ulcerative colitis
✓ Use of Sulfonamides for Prophylaxis: streptococcal infections and
recurrences of rheumatic fever among susceptible
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 TRIMETHOPRIM-SULFAMETHOXAZOLE

✓ usually is 20 to 100 times more potent than the Sulfamethoxazole

✓ the combination of trimethoprim and sulfamethoxazole results from its
actions on two steps of the enzymatic pathway for the synthesis of
tetrahydrofolic acid
✓ Resistance often is due to the acquisition of a plasmid that codes for an
altered dihydrofolate reductase
✓ The pharmacokinetic profiles of sulfamethoxazole and trimethoprim are
closely but not perfectly matched
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 QUINOLONES

✓ The first quinolone, nalidixic acid, was isolated as a by-product of the

synthesis of chloroquine
✓ fluorinated 4-quinolones include ciprofloxacin, moxifloxacin , and
gatifloxacin have broad antimicrobial activity
✓ Few side effects appear to accompany the use of these
fluoroquinolones,
✓ Microbial resistance to their action does not develop rapidly

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 Quinolones Cont..
Mechanism of action

✓ Interfere with bacterial DNA synthesis by inhibiting topoisomerase II

(DNA gyrase), especially in gram-negative organisms, and
topoisomerase IV, especially in gram-positive organisms.

✓ Block the relaxation of supercoiled DNA that is catalyzed by DNA

gyrase, a step required for normal transcription and duplication.

✓ Exhibit postantibiotic effects and are bactericidal

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 Quinolones Cont..
Microbial Resistance

✓ Efflux pumps (S.aureus, S.pneumoniae)

✓ Changes in the sensitivity of the target enzymes via point mutations in

the antibiotic binding region (gonoccoci)

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 Quinolones Cont..
Therapeutic use

✓ Respiratory tract infection

✓ Skin and soft tissue infections
✓ Gonorrhoea
✓ Chlamydia trachomatis infections

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Antimycobacterial drugs

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 Antimycobacterial drugs cont..

✓ Major drugs used in TB: isoniazid (INH), rifampin, ethambutol,

pyrazinamide, and streptomycin.

✓ Isoniazid (INH) is a structural congener of pyridoxine. Its mechanism of

action involves inhibition of the synthesis of mycolic acids, essential
components of mycobacterial cell walls.

✓ Rifampin, a derivative of rifamycin, is bactericidal against M

tuberculosis. The drug inhibits DNA-dependent RNA polymerase
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 Antimycobacterial drugs cont..

✓ Ethambutol (ETB) inhibits arabinosyltransferases involved in the

synthesis of arabinogalactan, a component of mycobacterial cell walls

✓ Pyrazinamide; MOA is not known; however, its bacteriostatic action

appears to require metabolic conversion via pyrazinamidases

✓ Combination commonly abbreviated as: HERZ

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THANKS!
Any questions?

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