Pharmacology-1 PHL 211 2 nd Term 9 th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: [email protected].

Pharmacology-1 PHL 211

2nd Term

9th Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected]

Antimicrobial Agents,

Antibiotics, Sulphonamides and

Antifungal Drugs

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:

enhance the beneficial effects minimize the undesirable effects increase solubility increase stability improve pharmacokinetics (i.e., wider distribution and longer half-life)

Antibiotics, Terminology

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, -lactams 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)

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

Basis of Choice of the Proper Antibiotic

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

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

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

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

Basis of Choice of the Proper Antibiotic

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

Bactericidal Interfere with cell wall biosynthesis (by

inhibiting cross-linking of peptidoglycans)

Large group including: Penicillins cephalosporins Carbapenems monobactams

Most penicillins (e.g., ampicillin) are destroyed by -lactamase Cephalosporins, carbapenems and

monobactams all are -lactamase resistant

Wide usage Penicillins are often first choice for fighting

infections (cephalosporins second)

Resistance is becoming an increasing problem (see later)

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Bacterial Cell Envelope

Mechanism of Action of -Lactams All -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

-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 -Lactams, so what!!

After a –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: -Lactams exert a bactericidal action on growing or multiplying germs

The transpeptidation reaction in that is

inhibited by -lactam antibiotics

-Lactam antibioticsΘ

Mechanism of Action, In motion