Penicillins- Mechanism of action, Antimicrobial spectrum & Antibacterial resistance -

The presentation include details of Pharmacology of Penicillins.

1. P E N I C I L L I N S ANUSHA SHAJI, B.Pharm , M.Pharm Assistant Professor Department of Pharmacology Nirmala College of Pharmacy, Muvattupuzha , Ernakulam , Kerala

2. CONTENTS Introduction Mechanism of Action of Penicillin P enicillin G Antimicrobial Spectrum Bacterial Resistance Uses

3. INTRODUCTION BETA LACTAMS PENICILLINS CEPHALOSPORINS CARBAPENAMS MONOBACTAMS Beta Lactam Ring

4. Structure of Beta lactam Antibiotics

5. PENICILLINS Penicillin was the first antibiotic to be used clinically in 1941 The most widely effective antibiotics The least toxic drugs known It was originally obtained from the fungus Penicillium notatum The present source is a high yielding mutant of P. chrysogenum Chemistry and Properties The penicillin nucleus consists of fused thiazolidine and beta lactam rings to which side chains are attached through an amide linkage Examples Amoxicillin Ampicillin Dicloxacillin Methicillin Oxacillin Penicillin G Penicillin V

6. Mechanism of Action- Penicillins All beta lactam antibiotics interfere with the synthesis of bacterial cell wall. The penicillins interfere with the last step of bacterial cell wall synthesis ( ie , transpeptidation or cross linking). Resulting in exposure of the osmotically less stable membrane Cell lysis occurs either through osmotic pressure or through the activation of lysins These drugs are thus bactericidal

7. 1. Penicillin Binding Proteins Penicillins inactivate numerous proteins on the bacterial cell membrane. These penicillin binding proteins (PBPs) are bacterial enzymes Involved in the synthsis of the cell wall and in the maintenance of the morphologic features of the bacterium. 2. Inhibition of transpeptidase Some PBPs catalyze formation of the cross linkage between peptidoglycan chains Penicillins inhibit this peptidase catalyzed reaction

8. Thus altering the formation of cross links essential for cell wall integrity As a result of this blockade of cell wall synthesis & accumulation of park nucleotide (UDP-N- acetylmuramic acid pentapeptide ) 3. Production of Autolysins Many bacteria, particularly the gram positive cocciproduces degradative enzymes (autolysins) That participate in the normal remodeling of the bacterial cell wall In the presence of a penicillin the degradative action of the autolysins proceeds in the absence of cell wall synthesis.

9. Note: The exact autolytic mechanism is unknown. Thus the antibacterial effect of a penicillin is the result of both: Inhibition of cell wall synthesis and destruction of existing cell wall by autolysins

10. Mechanism of Action- Flow Chart Penicillins Prevents peptidoglycan synthesis Inhibit transpeptidase Bind and inactivate PBPs (Penicillin Binding Proteins) on the cell wall of susceptible bacteria Cell wall deficient (CWD) forms are produced Autolysis ) Cell death (Bactericidal effect)

11. Penicillin G- Antimicrobial Spectrum PnG is anarrow spectrum antibiotic Limited activity- gram positive, few gram negative and anaerobes Streptococci - Highly sensitive Staph. aureus - originally very sensitive, acquired resistsnce Neisseria gonorrhoeae & N. meningitidis (gram negative cocci )- susceptible to PnG Gram postive bacilli - B. anthracis , Corynebacterium diphtheriae , All Clostridia, Listeria are highly sensitive. Aerobic gram negative bacilli- Mycobacterium tuberculosis , Rickettsiae , protozoa, Fungi and virus are totally insensitive to pnG .

12. BACTERIAL RESISTANCE Many bacteria are inherently insensitive to PnG Because in them the target enzymes and PBPs are located deeper under lipoprotein barrier Where PnG is unable to penetrate or have low affinity for PnG The primary mechanism of acquired resistance is production of penicillinase . Penicillinase It is a narrow spectrum beta lactamase which opens the beta lactam ring and inactivates Penicillin G. Penicillinase has been successfully used to destroy PnG in patient’s blood sample so that it does not interfere with bacterial growth when such blood is cultured

13. Uses Streptococcal infections Pneumococcal infections Meningococcal infections Gonorrhoea Syphilis Diphtheria Tetanus Prophylactic use- Rheumatic fever, bacterial endocarditis