Antimicrobial and Antibacterial Agents

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1 Antimicrobial and Antibacterial Agents

2 Contents Introduction Classification of antimicrobial drugs Special terms Mechanism of action Resistance of antimicrobial agent

3 Introduction Joseph Lister Father of Antiseptics.Introduced use of carbolic acid (Phenol-antiseptic 0.2%, disinficants-2%) Paul Ehrlich first suggest using chemical compounds (Magic Bullets)to treat microbial diseases Salvarsan Alexander Fleming observed that the mold Penicillium notatum inhibited the growth of Staphylococcus aureus colonies - unable to purify the compound. Gerhard Domagk Therapeutic value of sulfonamides against streptococcus and other organisms. Penicillin became available in quantities sufficient for clinical use in After that,streptomycin, chloramphenicol, and tetracycline were discovered. Since then, numerous classes of antimicorabial agents have been identified, and a lot of drugs are available for use today. Antimicrobials are among the most commonly used drugs.

4 Classification of antimicrobial drugs Antibacterial drugs Antiviral drugs Antifungal drugs Viruses use host enzymes inside host cells Fungi and protozoa have own eukaryotic enzymes The more similar the pathogen and host enzymes, the more side effects the antimicrobials will have The relationship of Host-Drug-Pathogen in chemotherapy

5 Antibacterial agent Antibacterial agent can be defined as substances from microorganisms (bacteria, fungi) or synthesized substance that produce bacteriostatic or bactericidal effects. Antibiotics an be defined as substances from microorganisms (bacteria, fungi) that produce bacteriostatic or bactericidal effects. No antibiotic is effective against all microbes Special terms Antimicrobial spectrum - Antimicrobial spectrum of a drug means the species of microorganisms that the drug can inhibit or kill. 1. Narrow spectrum -The agents act against a single or limited group of microorganisms, for example, isoniazid is active only against mycobacteria 2. Broad spectrum -The agent affect a wide variety of microbial species and are referred to as broad spectrum antibiotics. For example, tetracyclines and chloramphenicol. Using broad spectrum antibiotics interfere the nature of the normal bacterial flora and can precipitate a superinfection of an organism.

6 Bacteriostatic drugs Bacteriostatic drugs agents arrest the growth or replication of the microorganism, but cannot kill them. Bactericidal drugs Special terms The agents which can kill the microorganisms are called bactericidal drugs. but also can destroy them. It should be noted that a drug may be bacteriostatic for one organism but bactericidal for another. Bactericidal vs Bacteriostatic

7 Special terms Chemotherapy- The use of drugs to treat a disease Selective toxicity: A drug that kills harmful microbes without damaging the host Chemotherapy index (CI) CI is a term used to evaluate the safety of chemotherapeutic drugs, the value is LD50/ED50 or LD5/ED95. CI= LD50/ED50 CI= LD5/ED95 Minimal inhibitory concentration (MIC) MIC is the lowest concentration of antimicrobial agents that prevents visible growth in hours incubation. Minimum Bactericidal Concentration (MBC)- The minimum concentration needs for kill 99.9% of testing microorganisms. If MBC 32 MIC, it indicates that the microorganism has resistance to the drug.

8 Microbial Sources of Antibiotics

9 Mechanism of action include: 1. Inhibition of metabolic pathways 2. Inhibition of cell wall synthesis 3.Interference with cell membrane integrity 4. Inhibition of protein synthesis 5.Inhibition of nucleic acid synthesis DNA gyrase Rifamycins Cell wall synthesis DNA-directed RNA polymerase Penicillins Cephalosporins Cycloserine THFA DNA mrna Folic acid metabolism Sulfonamides DHFA Ribosomes 30S 30S 50S 50S 30S 50S Protein synthesis (30S inhibitors) Chloramphenicol Streptomycin Tetracylines Periplasmic space Protein synthesis (50S inhibitors) PABA Polymyxins B Cell membrane Antimicrobial C site of action

10 Gram-positive Gram-negative

11 Inhibition of metabolic pathways Relatively few Most useful are folate inhibitors Mode of actions to inhibit the production of folic acid Antimicrobials in this class include Sulfonamides Trimethoprim Inhibition of metabolic pathways

12 Sulfonamides Group of related compounds Collectively called sulfa drugs Inhibit growth of Gram + and Gram - organisms Through competitive inhibition of enzyme that aids in production of folic acid Structurally similar to para-aminobenzoic acid Substrate in folic acid pathway Human cells lack specific enzyme in folic acid pathway Basis for selective toxicity Resistance due to plasmid Inhibition of metabolic pathways Plasmid codes for enzyme that has lower affinity to drug

13 Trimethoprim Inhibition of metabolic pathways Inhibits folic acid production Interferes with activity of enzyme following enzyme inhibited by sulfonamides Often used synergistically with sulfonamide Most common mechanism of resistance is plasmid encoded alternative enzyme Genes encoding resistant to sulfonamide and trimethoprim are often carried on same plasmid

14 Inhibition of cell wall synthesis Inhibition of Cell wall synthesis Bacteria cell wall unique in construction Contains peptidoglycan Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell Due to the lack of cell wall in animal cells and differences in cell wall in plant cells These drugs have very high therapeutic index Low toxicity with high effectiveness Antimicrobials of this class include β lactam drugs Vancomycin Bacitracin

15 Inhibition of cell wall synthesis Penicillins and cephalosporins Part of group of drugs called β lactams Have shared chemical structure called β-lactam ring Competitively inhibits function of penicillin-binding proteins Inhibits peptide bridge formation between glycan molecules This causes the cell wall to develop weak points at the growth sites and become fragile.

16 Inhibition of cell wall synthesis The weakness in the cell wall causes the cell to lyze. Penicillins and cephalosporins are considered bactericidal. Penicillins are more effective against Gram+ bacteria. This is because Gram + bacteria have penicillin binding proteins on their walls. Penicillin (over 50 compounds) Share 4-sided ring (b lactam ring) Natural penicillins Narrow range of action Susceptible to penicillinase (b lactamase)

17 Inhibition of cell wall synthesis The cephalosporins Cephalosporins Chemical structures make them resistant to inactivation by certain β-lactamases Tend to have low affinity to penicillin-binding proteins of Gram + bacteria, therefore, are most effective against Gram bacteria. Chemically modified to produce family of related compounds First, second, third and fourth generation cephalosporins

18 Inhibition of cell wall synthesis Vancomycin Inhibits formation of glycan chains Inhibits formation of peptidoglycans and cell wall construction Does not cross lipid membrane of Gram - Gram - organisms innately resistant Important in treating infections caused by penicillin resistant Gram + organisms Must be given intravenously due to poor absorption from intestinal tract Acquired resistance most often due to alterations in side chain of NAM molecule Prevents binding of vancomycin to NAM component of glycan

19 Inhibition of cell wall synthesis Bacitracin Interferes with transport of peptidoglycan precursors across cytoplasmic membrane Toxicity limits use to topical applications Common ingredient in non-prescription first-aid ointments

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