1. Pharmacology-1 PHL 211 2 nd Term 9 th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2. Antimicrobial Agents, Antibiotics, Sulphonamides and Antifungal Drugs

3. 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)

4. 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

5. 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

6.  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

7. 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

8. 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)

9. Bacterial Cell Envelope

10. 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

11. 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

13. The transpeptidation reaction in that is inhibited by  - lactam antibiotics  -Lactam antibiotics Θ

14. Mechanism of Action, In motion