Transcript 2nd Term 9th Lecture

Pharmacology-1 PHL 211
2nd Term
9th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Antibiotics,
Overview
 Definition
In the strictest sense, antibiotics are antibacterial substances produced by
various species of microorganisms (bacteria, fungi and actinomycetes) that
suppress the growth of other microorganisms
 Common usage often extends the term antibiotics to include synthetic antimicrobial
agents, such as sulfonamides and quinolones
 The first antibiotic to be discovered was penicillin, a natural product of
Penicillium mold. Innumerable microbial products have been investigated since
then

Semi-synthetic antibiotics: chemically modified natural antibiotics
Why modified? They are modified in an attempt to:
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enhance the beneficial effects
minimize the undesirable effects
increase solubility
increase stability
improve pharmacokinetics (i.e., wider distribution and longer half-life)
Antibiotics,
Terminology
 Bacteriostatic vs. bactericidal drugs
 Bacteriostatic agents inhibit bacterial cell replication but require the host's
immune factors to clear the infection, whereas bactericidal agents kill the
bacteria
 If host immunity is suppressed or the infection is in an area of poor
immunologic surveillance (e.g., CSF), bacteriostatic agents may not be as
effective as bactericidal agents
 Minimal inhibitory concentration (MIC)
 The lowest concentration of antibiotic that inhibits bacterial growth
 Synergism vs. antagonism
 Drug synergism occurs when drugs can interact in ways that enhance or
magnify one or more effects, or side effects, of those drugs. For example, blactams and aminoglycosides
 The opposite of synergy is antagonism, the phenomenon where two agents
in combination have an overall effect that is less than that predicted from
their individual effects. For example, chloramphenicol (generally
bacteriostatic) antagonizes the actions of penicillins (bactericidal)
Basis of Choice of the Proper Antibiotic

The decision to prescribe an antibiotic is based upon proof or strong
suspicion that the patient has a bacterial infection

Probable viral infectious or noninfectious processes should not be treated with
antibiotics

However, in the critically ill patient in whom there is some chance that a
bacterial infection may be a contributing factor, it is prudent to administer
antibiotics effective against the most likely pathogens

Whenever possible the antibiotic selection should be based upon the
isolation of a pathogen (followed by cultivation and identification and the
susceptibility to antibiotics)

But most patients who require antibiotic therapy present with an acute
problem that mandates initial empiric therapy
Basis of Choice of the Proper Antibiotic
 Empiric Therapy
 the specific antibiotic chosen is based upon:
1. knowledge of the pathogens likely to cause a specific infection and its
susceptibility to a particular antibiotic
2. the ability of the pathogen to inactivate the antibiotic
3. spectrum of activity of the antibiotic
4. safety of the antibiotic and its most common side effects
5. site of infection
6. patient’s history
7. cost of the therapy, compared to agents of equal safety and efficacy

If more than one antibiotic is active against the likely pathogens at the
site of infection, the specific agent should be chosen on the basis of
relative toxicity, convenience of administration and cost
Classification of Antibiotics by Mechanism of Action
Inhibition of cell-wall synthesis
Vancomycin
Penicillins
Cephalosporins
Aztreonam
Imipenem
Inhibition of nucleic acid synthesis
Rifampin
Quinolones
Metronidazole
Inhibition of protein synthesis
Aminoglycosides
Spectinomycin
Tetracyclines
Chloramphenicol
Erythromycin
Clindamycin
Inhibition of folate synthesis
Sulfonamides
Trimethoprim
Beta-Lactam Antibiotics, Overview
 Large group including:
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Penicillins
cephalosporins
Carbapenems
monobactams
 Bactericidal
 Interfere with cell wall biosynthesis (by
inhibiting cross-linking of peptidoglycans)
 Most penicillins (e.g., ampicillin) are
destroyed by b-lactamase
 Cephalosporins, carbapenems and
monobactams all are b-lactamase resistant
 Wide usage
 Penicillins are often first choice for fighting
infections (cephalosporins second)
 Resistance is becoming an increasing
problem (see later)
Bacterial Cell Envelope
•
Mechanism of Action of b-Lactams
 All b-lactam antibiotics, including penicillins, kill susceptible bacteria by specifically
inhibiting the transpeptidase that catalyzes the final step in cell wall biosynthesis,
the cross-linking of peptidoglycan
 The cell wall is a rigid outer layer that is not found in animal cells:
 It completely surrounds the cytoplasmic membrane, maintaining the shape of the cell
and preventing cell lysis from high osmotic pressure
 It is composed of:
Outer membrane, a lipid bilayer, is present in gram-negative but not gram-positive
organisms. It is penetrated by porins, proteins that form channels providing
hydrophilic access to the cytoplasmic membrane
A complex cross-linked polymer, peptidoglycan, consisting of polysaccharides and
polypeptides
 The polysaccharide contains alternating amino sugars, N-acetylglucosamine (G) and
N-acetylmuramic acid (M)
 A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide
terminates in D-alanyl-D-alanine
 Penicillin-binding proteins (PBPs) catalyze the transpeptidase reaction that removes
the terminal alanine to form a crosslink with a nearby peptide, which gives cell wall its
structural rigidity
 b-Lactam antibiotics are structural analogs of the natural D-Ala-D-Ala substrate and
they covalently bind PBPs at the active site
Mechanism of Action of b-Lactams, so what!!
After a b–lactam antibiotic attaches to the PBP, the transpeptidation reaction is
inhibited and peptidoglycan synthesis is blocked. Because of the cell wall
defects, the bacteria swell
and burst
The final bactericidal event is the inactivation of an inhibitor of the autolytic
enzymes in the cell wall  this leads to lysis of the bacterium
 NB: b-Lactams exert a bactericidal action on growing or multiplying germs
The
transpeptidation
reaction in that is
inhibited by blactam antibiotics
Θ
b-Lactam
antibiotics
Mechanism of Action, In motion