Antibiotics Lecture 04

Bio 319: Antibiotics
Lecture Four

Topic
Inhibitors of Nucleic acid synthesis
Inhibitors of synthesis of essential metabolites
Introduction to antibiotics resistance

Lecturer: Dr. G. Kattam Maiyoh

03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 1

Reminder


The Action of Antimicrobial Drugs


Inhibitors of Cell Wall Synthesis


Protein synthesis inhibitors
– Aminoglycosides
– Tetracyclins
- Spectinomycin
– Macrolides
– Chloramphenicol
– Clindamycin


Inhibitors of Nucleic Acid Synthesis

~Inhibitors of DNA synthesis
~Inhibitors of RNA synthesis


Inhibitors of RNA Synthesis
For this class of antibiotics, selectivity is due to
differences between prokaryotic and eukaryotic RNA
polymerase i.e.
All RNA polymerases are multi-protein complexes,
however, the number of proteins that are assembled
to form the active enzyme is much larger in eukaryotes;
•The basic catalytic core is made up of 12 subunits.
•By comparison, bacterial RNAP has 5 subunits.


Rifampin, Rifamycin, Rifampicin, Rifabutin
(bactericidal)
• Mode of action - These antimicrobials bind to DNA-dependent RNA
polymerase and inhibit initiation of mRNA synthesis.
• Spectrum of activity - Broad spectrum but is used most commonly
in the treatment of tuberculosis
• Resistance – Common
– For example;
– Resistance to rifampicin develops quickly during treatment, so
monotherapy should not be used to treat these infections — it
should be used in combination with other antibiotics.
– Resistance to rifampicin arises from mutations that alter
residues of the rifampicin binding site on RNA polymerase,
resulting in decreased affinity for rifampicin.
• Combination therapy - Since resistance is common, rifampin is
usually used in combination therapy.

Inhibitors of DNA Synthesis
For this class of antibiotics, selectivity due to differences between prokaryotic
and eukaryotic DNA replication enzymes
Consider the following:
Eukaryotic replication is more complicated.
•First, they have multiple ori per chromosome that allow for
bidirectional synthesis of the linear chromosome.
•They also use several DNA polymerases (I, II, III), and ligase (seals the
nicks in the DNA strand), and RNA primer (gives a 3' end for the DNA
polymerase to start synthesis).

•As for other differences in their synthesis of DNA is their speed,
prokaryotes can replicate their chromosome at about 1,000 bp/sec, while
eukaryotes can replicate their chromosomes at about 100 bp/sec.
•They also differ in the number of ori, eukaryotes (as it was stated above)
has multiple ori, while prokaryotes have only one.


The Quinolones

• Current drugs are
fluoridated 4-quinolones
• Broad coverage (some
broader than others)
• Targets DNA gyrase (G-)
and topoisomerase IV
(G+)
• Resistance due to efflux
and mutations in targets


Pharmacological attributes of Quinolones
• Favorable pharmacological attributes
– Orally administered, quickly
absorbed, even with a full
stomach
– Excellent bioavailability in a wide
range of tissues and body fluids
(including inside cells)
• Mostly cleared by the kidneys
– Exceptions are pefloxacin and
moxifloxacin which are
metabolized by liver
• Ciprofloxacin, ofloxacin, and
pefloxacin are excreted in breast milk

“Got Cipro?”


Therapeutic Uses
of Quinolones
• Urinary tract
infections
• Prostatitis
• STD’s
– Chlamydia
– Chancroid - painful
sores on the genitalia
– Not syphilis or
gonorrhea (due to
increased resistance)


Therapeutic Uses of Quinolones
• GI and abdominal
– Travelers diarrhea
– Shigellosis
– Typhoid fever
• Respiratory tract
– New agents for strep. pneumonia


Therapeutic Uses
of Quinolones
• Bone, joint, soft tissue
– Ideal for chronic
osteomylitis - infection of
the bone or bone marrow
• Resistance developing in
S. aureus, P. aeruginosa,
and S. marcesens
– Good against
polymicrobial infections
like diabetic foot ulcers


Therapeutic Uses
of Quinolones
• Ciprofloxacin for anthrax
and tuleremia (rabbit fever, deer
fly fever, Ohara's fever)
• Combined with other drugs,
useful for atypical
Mycobacterium sp.

Pulmonary Anthrax

Toxicity/Contraindications of Quinolones
• Nausea, vomiting, abdominal discomfort (common)
• Diarrhea and antibiotic-associated colitis (uncommon to rare)
• CNS side effects
– Mild headache and dizziness (common to rare)
– Hallucinations, delirium, and seizures (rare)
• Arthropy in immature animals (common)
– Quinolones not given to children unless benefits outweigh the risks
• Leukopenia, eosinophila, heart arythmias (rare)

delirium - disorder involving incoherent speech, hallucinations, etc., caused by
intoxication, fever, etc


Antimetabolite Antimicrobials


Inhibitors of Folic Acid Synthesis
p-aminobenzoic acid + Pteridine
Pteridine
• Basis of Selectivity Sulfonamides
synthetase

• Review of Folic Dihydropteroic acid
Acid Metabolism Dihydrofolate
synthetase

Dihydrofolic acid
Dihydrofolate
Trimethoprim reductase

Tetrahydrofolic acid

Thymidine Methionine
03/21/13 GKM/BIO319:Antibiotics/Sem2/2013
Purines 18

Sulfonamides, Sulfones (bacteriostatic)
• Mode of action - These antimicrobials are analogues of para-
aminobenzoic acid and competitively inhibit formation of dihydropteroic
acid.

• Spectrum of activity - Broad range activity against gram-positive and
gram-negative bacteria; used primarily in urinary tract and Nocardia
infections.

• Resistance - Common

• Combination therapy - The sulfonamides are used in combination with
trimethoprim; this combination blocks two distinct steps in folic acid
metabolism and prevents the emergence of resistant strains.


Trimethoprim, Methotrexate,
Pyrimethamine (bacteriostatic)
• Mode of action - These antimicrobials binds to dihydrofolate reductase
and inhibit formation of tetrahydrofolic acid.

• Spectrum of activity - Broad range activity against gram-positive and
gram-negative bacteria; used primarily in urinary tract and Nocardia
infections.

• Resistance - Common

• Combination therapy - These antimicrobials are used in combination with
the sulfonamides; this combination blocks two distinct steps in folic acid
metabolism and prevents the emergence of resistant strains.


Sulfonamides
• Analogues of para-aminobenzoic
acid
• Broad spectrum
• Competitive inhibitors of
dihydropteroate synthase – needed
for folic acid synthesis

Gerhard Domagk gets a Nobel
for Medicine, 1939.


Sulfonamides
• Mostly absorbed from GI tract
• Binds variably to serum albumin
• Wide tissue distribution, including
transplacentally
• Variably inactivated in liver by
acetylation and then excreted in
urine
• Some agents can precipitate in acid
urine


1. Rapidly Absorbed and Eliminated
Sulfonamides
• Sulfisoxazole,
sulfamethoxazole, sulfadiazine

• Bind extensively to plasma
proteins

• Highly concentrated in urine
(cidal)

• Sulfamethoxazole combined
with trimethoprim (Bactrim) is
widely used to treat a variety
of infections (esp. UTI)


2. Poorly Absorbed Sulfonamides
• E.g. Sulfasalazine
• Poorly absorbed in GI tract
• Used to treat ulcerative colitis
and irritable bowel syndrome
• Gut flora metabolize drug into
2 compounds, 1 toxic-
sulfapyridine, 1 therapeutic
(5-aminosalicylate)
• Hence is a prodrug – effective
after breakdown
Ulcerative Colitis


Sulfonamides for Topical Use

• E.g. 1.Sulfacetamide
– Good penetration in eye
– Non-irritating
• 2. Silver sulfadiazine
– Prevention and treatment of
burn wound infections

Bacterial corneal infection


Long Acting Sulfonamide
• Serum half-life is
measured in days rather
than minutes or hours
• E.g. Sulfadoxine
• Combined with
pyirethamine to treat
malaria
Plasmodium vivax


Therapeutic Uses of Sulfonamides
• Urinary tract infections
• Nocardiosis -serious infection
caused by a fungus-like bacterium
that begins in the lungs and can
spread to the brain.

• Toxoplasmosis - caused
by protozoan (avoid using in
pregnant women)

Nocardia asteroides


Toxicity/Contraindications
of Sulfonamides - UT

• Crystallization in acid
urine
– Common to uncommon
depending on drug.

– Alkalize urine or increase
hydration


of Sulfonamides - blood
• Acute hemolytic anemia
– Rare to extremely rare
– Associated with glucose-6-phosphate
dehydrogenase activity in RBC
• Agranulocytosis - failure of the bone marrow to make enough white
blood cells (neutrophils). (extremely rare)

• Aplastic anemia - marrow doesn't make enough new blood cells.
(extremely rare)


of Sulfonamides - immune
• Hypersensitivity reactions
(common to uncommon)
– Skin and mucous membrane
manifestations (rashes)
– Serum sickness - type III hypersensitivity
reaction that results from the injection of
heterologous or foreign protein or serum
– Focal or diffuse necrosis of the liver
(rare)


Toxic Epidermal Necrolysis (TEN)


of Sulfonamides - miscellaneous
• Nausea, anorexia, vomiting
(common)
• Kernicterus; damage caused by
excessive jaundice
– Displacement of bilirubin from
plasma albumin to brain
resulting in
encephalopathy(disease of
the brain)
– Never give sulfa drugs to a
pregnant or lactating woman
Bilirubin deposits in neonatal • Potentiation of oral coagulants,
brain sulfonylurea hypoglycemic drugs,
and hydrantoin anticonvulsants

INJURY TO THE PLASMA MEMBRANE - Brief

• All cells are bound by a cell membrane.
• And although the membranes of all cells are quite
similar, those of bacteria and fungi differ from
eukaryotic cells.
• These slight differences allow for selective action of
some antimicrobial agents.
• Certain antibiotics, like polymyxins, act as detergents
to dissolve bacterial cell membranes by binding to
phospholipids present in the membranes.


Antibiotic Resistance
• A variety of mutations can lead to antibiotic resistance
• Mechanisms of antibiotic resistance
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
• Resistance genes are often on plasmids or transposons
that can be transferred between bacteria.


Transmission of drug resistance
• Transmission of drug resistance
– Bacterial plasmids
– Transposons
– Bacteriophages


Resistance to Antibiotics


Role of “misuse”
• Misuse of antibiotics selects for resistance
mutants.
• Misuse includes;
– Using outdated or weakened antibiotics
– Using antibiotics for the common cold and other
inappropriate conditions
– Using antibiotics in animal feed
– Failing complete the prescribed regimen
– Using someone else's leftover prescription


Microbe Library
American Society for Microbiology
www.microbelibrary.org


Antimicrobial Drug Resistance
Mechanisms

• Altered permeability
– Altered efflux
• tetracycline

Microbe Library


Mechanisms
• Inactivation
– β-lactamase
– Chloramphenicol
acetyl transferase

Microbe Library


Mechanisms
• Altered target site
– Penicillin binding proteins
(penicillins)
– RNA polymerase (rifampin)
– 30S ribosome
(streptomycin)

Microbe Library


Antimicrobial Drug Resistance Mechanisms
• Replacement of a sensitive pathway
– Acquisition of a resistant enzyme
(sulfonamides, trimethoprim)


Antibiotics Lecture 04

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