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Lecture 5 Antibiotics
Lecture 5 Antibiotics
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Translation
Review and Overview of Bacterial Targets
• Bacterial cell walls
– Except for Mycoplasma and relatives, all
bacteria of the Domain Eubacteria possess
peptidoglycan
– Peptidoglycan provides shape and structural
support to bacterial cells
– Bacterial cytoplasm is generally hypertonic
compared to their environment
• Net flow of water: into cell
• Wall under high osmotic pressure
Cell walls continued
• Chemical structure of peptidoglycan
contributes to its function
– Polysaccharide chains composed of 2
alternating sugars, N-acetylglucosamine (NAG)
and N-acetylmuramic acid (NAM)
– Cross-linked in 3 dimensions with amino acid
chains
– A breach in peptidoglycan endangers the
bacterium
Peptidoglycan Molecule
• Phenoxymethylpenicillin (Penicillin V) is
acid stable and is given orally for minor
infections
• it is otherwise similar to benzylpenicillin
Penicillins
Examples
• Resistance - Common
Macrolides
Examples and clinical pharmacokinetics
• Resistance - Common
• Diarrhoea is common.
• Superinfection with a strain of Clostridium
difficile which causes serious inflammation
of the large bowel (Pseudomembranous
colitis)
Chloramphenicol
• This inhibits bacterial protein synthesis.
• It is well absorbed and widely distributed ,
including to the CNS.
• It is metabolized by glucoronidation in the
liver.
• Although an effective broad-spectrum
antibiotics, its uses are limited by its serious
toxicity.
Chloramphenicol
• The major indication is to treat bacterial
meningitis caused by Haemophilus
influenzae, or to Neisseria menigitidis or if
organism is unknown.It is also specially
used for Rikettsia (typhus).
Chloramphenicol
Adverse effects
tetrahydrofolic acid
Sulfonamides and trimethoprim
• Sulfonamides are rarely used alone today.
• Trimethoprim is not chemically related but
is considered here because their modes of
action are complementary.
Sulfonamides, Sulfones (bacteriostatic)
• Mode of action - These antimicrobials are analogues of
para-aminobenzoic acid and competitively inhibit formation
of dihydropteroic acid.
• Resistance - Common
Dihydropteroic acid
Dihydrofolate
synthetase
Dihydrofolic acid
Dihydrofolate
Trimethoprim reductase
Tetrahydrofolic acid
Thymidine Methionine
Purines
Sulfonamides and trimethoprim
Mode of action
• Gastrointestinal upsets
• Less common but more serious:
sulfonamides: allergy, rash, fever,
renal toxicity
trimethoprim: anemia, thrombocytopenia
-cotrimoxazole: aplastic anemia
4-Interference with nucleic acid
synthesis
• Bacterial DNA is negatively supercoiled
– Supercoiling is maintained by gyrase, a type II
topoisomerase.
– Inhibition of gyrase and type IV topoisomerase interferes
with DNA replication, causes cell death
– Eukaryotic topoisomerases differ in structure
Quinolones (bactericidal)
nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin,
levofloxacin, lomefloxacin, sparfloxacin
• Gastrointestinal upsets
• Fluoroquinolones may block the inhibitory
neurotransmitter, and this may cause confusion
in the elderly and lower the fitting threshold.
• Allergy and anaphylaxis
Quinolones
Adverse effects
• Gastrointestinal upsets
• Allergy
• Polyneuritis
Fucidin
• Fucidin is active only against Staphylococcus
aureus (by inhibiting bacterial protein
synthesis) and is not affected -lactamase.
• It is usually only used with flucloxacillin to
reduce the development of resistance.
• It is well absorbed and widely distributed,
including to bone
• It can be given orally or parenterally.
• It is metabolized in the liver.
Antibiotics for leprosy
• Leprosy is caused by infection with
Mycobacteria leprae.
• A mixture of drugs are used to treat leprosy,
depending on the type and severity of the
infection and the local resistance patterns.
Antibiotics for leprosy
• Rifampicin is used, which is related to the
sulphoamides.
• Rifampicin and Rifamycin block synthesis
of m-RNA.
• Its adverse effects include haemolysis,
gastrointestinal upsets and rashes.
5- Cell membranes as targets
• Bacterial cell membranes are essentially the
same in structure as those of eukaryotes
– Antibiotics also affect Gram neg. cell walls, ie.
Outer membrane together with cell membrane
– Anti-membrane drugs are less selectively toxic
than other antibiotics.
– Many antifungal drugs ( Polyenes as
Amphotericin B, Nystatin) make use of cell
membrane differences.
Cell membrane disruptors
3. Agar diffusion
Kirby-Bauer Disk Diffusion Test
Susceptibility Tests
“Kirby-Bauer Disk-plate test” (cont’d)
Determination of MIC
Str
Tet Ery
8 4 2 1 0 Chl Amp
Tetracycline (μg/ml)
MIC = 2 μg/ml
Resistance (cont.)
• Bacteria produce enzymes at or within the cell
surface –inactivate drug
• Bacteria possess impermeable cell membrane
prevent influx of drug.
• Transport mechanism for certain drug is energy
dependent- not effective in anaerobic
environment.
• ATB as organic acids penetration is pH –
dependent.