Mechanism of action of antimicrobial agents

IT INCLUDES THE DIFFERENT TYPES OF ANTIBIOTICS OF DAILY USE

1. MECHANISM OF ACTION OF ANTIMICROBIAL AGENTS Reshma Soman MPhil Biosciences

2. INTRODUCTION The chemical and physical agents are used to treat inanimate objects in order to destroy microorganisms or inhibit their growth . Microorganisms also grow on and within other organisms, and microbial colonization can lead to disease, disability, and death. Thus the control or destruction of microorganisms residing within the bodies of humans and other animals is of great importance . 2

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4. Introduction ANTIBIOTICS: Chemical substance produced by micro organism that inhibit the growth of other microbes. ANTIMICROBIAL AGENTS: Chemical substance or biological source produced by chemical synthesis that kills or inhibit the growth of other organism. 4

5. General Characteristics of Antimicrobial Drugs A successful chemotherapeutic agent must have selective toxicity. It must kill or inhibit the microbial pathogen while damaging the host as little as possible. The degree of selective toxicity expressed in terms of therapeutic dose and toxic dose. The therapeutic dose, the drug level required for clinical treatment of a particular infection. The toxic dose, the drug level at which the agent becomes too toxic for the host. Therapeutic index: The ratio of toxic dose to therapeutic dose. 5

6. Classification Of Antibiotics 6

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9. Classification Of Antibiotics 9

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11. ANTIBACTERIAL DRUGS 11

12. ANTIBACTERIAL DRUGS Based on mechanism of action they can be classified into: 1.INHIBITORS OF CELL WALL SYNTHESIS 2. PROTEIN SYNTHESIS INHIBITORS 3.METABOLIC ANTAGONISTS 4.NUCLEIC ACID SYNTHESIS INHIBITORS 12

13. 1. INHIBITORS OF CELLWALL SYNTHESIS 13

14. INHIBITORS OF CELLWALL SYNTHESIS Selective inhibitors- they target the structure and function not found in eukaryotic cells . 14

15. PENICILLINS Most of them are derivatives of 6-amino penicillanic acid. ( eg : penicillin G or benzyl penicillin). Crucial feature –beta lactam ring. Penicillin resistant bacteria have pencillinase activity. Structure of penicillin resembles the terminal D- alanyl -D -alanine found on the peptide side chain of the peptidoglycan subunit. 15

16. Penicillins Structural similarity blocks the enzyme catalyzing the trans- peptidation reaction that forms the peptidoglycan cross links. Penicillin G is effective against bacteria causing gonorrhea and meningitis. Penicillin have broad spectrum activity. Ampicillin effective against Gram negative bacteria. 16

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18. CEPHALOSPORINS Isolated in 1948 from the fungus Cephalosporium . Contain beta lactam structure that is very similar to penicillin. Inhibit the trans- peptidation reaction during peptidoglycan synthesis. They are given to penicillin allergic patients . 18

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20. VANCOMYCIN Glycopeptide antibiotic, produced by bacterium Streptomyces orientalis . Cup shaped molecule peptide linked to diasaccharide . Peptide portion blocks the trans- peptidation reaction by binding specifically to D- alanyl – D- alanine in peptidoglycan. Bactericidal for Gram positive Staphylococcus, Clostridium, Bacillus, Streptococcus, Enterococcus . Resistance when bacteria change terminal D- alanine to D- lactate or D-serine thus altering the target. 20

21. This is also called the ‘drug of last resort’. 21

22. Vancomycin 22

23. TECOPLANIN Glycopeptide antibiotic. Produced by Actinoplanes teichomyceticus . It is similar to the structure and action of vancomycin , but fewer side effects. Active against Staphylococci, Enterococci, Streptococci, Clostridia, Listeria , and many gram positive pathogens . 23

24. Tecoplanin 24

25. 2. PROTEIN SYNTHESIS INHIBITORS 25

26. PROTEIN SYNTHESIS INHIBITORS Inhibit protein synthesis, binding with bacterial chromosome and other component of protein synthesis. Discriminate between eukaryotic and bacterial ribosomes. Therapeutic index is fairly high. 26

27. AMINOGLYCOSIDES Contain a cyclohexane ring and aminosugars . Streptomycin, kanamycin, neomycin and tobramycin synthesized by different species of Streptomyces , where as gentamycin from related genus Micromonospora purpura . 27

28. Aminoglycosides Gentamycin is used to treat Gram negative bacteria - Proteu s , Escherichia, Klebsiella , Serretia infections. Aminoglycosides can be quite toxic - cause hearing and renal damage, loss of balance, nausea and allergic reaction. They bind to 30S ribosomal subunit to interfere protein synthesis. Binding to incorrect subunit, the aminoglycoside allow the incorrect amino acid to be brought to ribosomes by tRNA . Bactericidal, most effective against Gram negative pathogens. 28

29. TETRACYCLINES Familiar antibiotic with common four ring structure to which a variety of side chains are attached . Oxytetracyline and chlortetracyclin are produced naturally by Streptomyces species, whereas others are semi synthetic. 29

30. Tetracyclines Mechanism of action similar to aminoglycosides . Action is only bacteriostatic . They are broad spectrum antibiotics - active against many bacteria including intracellular Rickettsias , Chlamydia, and Mycoplasma. 30

31. MACROLIDS Contain ring structure consisting of 12 to 22 carbons called lactone ring, the lactone ring is linked to one or more sugars. Erythromycin binds to 50S subunit to inhibit bacterial protein synthesis. Erythromycin relatively broad spectrum antibiotic - effective against Gram positive bacteria Mycoplasma and few Gram negative bacteria. Used to patients who are allergic to penicillin and in the treatment of whooping cough, diptheria , diarrhoea caused by Campylobacter, and Pneumonia from Legionella or Mycoplasma infections . 31

32. Macrolids Usually bacteriostatic. 32

33. Macrolids Clindamycin effective against variety of bacteria including Staphylococci and anaerobes such as bacteroides . Azithromycin active against Chlamydia trachomatis. 33

34. CHLORAMPHENICOL First produced by Streptomyces venezuelae . Like erythromycin ,this antibiotic binds to 50S subunit to inhibit bacterial protein synthesis. It has very broad spectrum activity. Quite toxic. Used in life threatening situation. 34

35. 3.METABOLIC ANTAGONISTS 35

36. 3.METABOLIC ANTAGONISTS They antagonize or block the functioning of metabolic pathway. Antimetabolites are structurally similar to the substrates of key enzymes and compete with the metabolites for binding site of these enzyme . Once bound to the enzyme they block enzyme activity, further progression of the pathway. They are broad spectrum but bacteriostatic . 36

37. SULFONAMIDES OR SULFA DRUGS Structurally related to sulfanyl amide, an analogue of P- aminobenzoic acid ( PABA). PABA important co-factor of many enzymes and needed for folic acid synthesis. Folic acid is a precursor of purins and pyramidines and other important cell component. It competes with PABA for active site of enzyme involved in folic acid synthesis. 37

38. Sulfonamides Or Sulfa Drugs 38

39. Sulfonamides Or Sulfa Drugs 39

40. Sulfonamides Or Sulfa Drugs Causing a decline in folate concentration, resulting purin and pyramidine concentration leads to ceasation protein synthesis and DNA replication. They are selectively toxic to many bacteria and protozoa because they manufacture their on folate , cannot effectively take up these co-factor whereas human do not synthesis folic acid. They have high therapeutic index. Increasing resistance limit their effectiveness . 40

41. TRIMETHOPRIN It is a synthetic antibiotic inhibit production of folic acid . It does not bind to dehydrofolate reductase (DHFR). The enzyme responsible for converting dehydrofolic acid to tetrahydrofolic acid by competing against the tetra hydro folic acid substrate. It is a broad spectrum antibiotic. Often used to treat respiratory tract infections, infections of middle ear, urinary tract infection and travellor’s diarrhea. Combined with sulfa drugs to increase efficacy of treatment by blocking two key step in folic acid pathway. 41

42. 4.NUCLEIC ACID SYNTHESIS INHIBITION 42

43. 4.NUCLEIC ACID SYNTHESIS INHIBITION They in inhibit nucleic acid synthesis function by inhibiting – 1 , DNA polymerases and topoisomerases 2, RNA polymerases to block replication or transcription, respectively. The drugs not selectively toxic because bacteria and eukaryotes do not differ greatly with respect to nucleic acid synthesis . 43

44. QUINOLONES Synthetic drug with 4 quinolone ring. First quinolone is naldixic acid. Currently used fluroquinolones - ciprofloxacin , norfloxacin , and ofloxacin . Quinolones act by inhibiting the bacterial DNA gyrase and topoisomerase II. DNA gyrase introduces negative twist in DNA and helps separate its strands. 44

45. Quinolones Inhibition of DNA gyrase disrupts DNA replication and repair, bacterial chromosome separation during division, and other cell processes involving DNA . Fluoroquinolones also inhibit topoisomerase II. Quinolones are bactericidal. Quinolones are broad - spectrum antibiotics. They are highly effective against enteric bacteria such as E coli and Klebsiella pneumoniae . They can be used with Haemophilus , Neiserria , P aeruginosa , and other Gram- negative pathogens . 45

46. Quinolones The quinolones also are active against gram-positive bacteria such as S. aureus , Streptococcus pyogenes , and Mycobacterium tuberculosis . Quinolones are effective, administered orally but can cause diverse side effects gastrointestinal upset. 46

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48. ANTIFUNGAL DRUGS 48

49. ANTIFUNGAL DRUGS Treatment of fungal infections generally has been less successful than that of bacterial infections. Because eukaryotic fungal cells are much more similar to human cells than are bacteria. Many drugs that inhibit or kill fungi are therefore quite toxic for humans. Most fungi have a detoxification system that modifies many antifungal agents . 49

50. Antifungal Drugs Effective antifungal agents frequently either extract membrane sterols or prevent their synthesis. Animal cells do not have cell walls, the enzyme chitin synthase is the target for fungal-active antibiotics such as polymyxin D and nikomycin . Fungal infections are often subdivided into superficial mycoses and systemic mycoses. Treatment for these two types of disease is very different . 50

51. Antifungal Drugs Three drugs containing imidazole — miconazole , ketoconazole, clotrimazole — are broad-spectrum agents. They are thought to disrupt fungal membrane permeability and inhibit sterol synthesis. Tolnaftate is used topically for the treatment of cutaneous infections. Nystatin , a polyene antibiotic from Streptomyces, is used to control Candida infections . 51

52. Antifungal Drugs It binds to sterols and damages the membrane, leading to fungal membrane leakage . The synthetic oral antimycotic agent 5-flucytosine is effective against most systemic fungi. The drug is converted to 5-fluorouracil by the fungi, incorporated into RNA in place of uracil, and disrupts RNA function. Fluconazole is used in the treatment of candidiasis, cryptococcal meningitis and coccidioidal meningitis. 52

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54. ANTI VIRAL DRUGS 54

55. ANTI VIRAL DRUGS Viruses enter host cells and make use of host cell enzymes and constituents. A drug that would block virus reproduction also was thought to be toxic for the host. Antiviral drugs disrupt either critical stages in the virus life cycle or the synthesis of virus-specific nucleic acids. 55

56. Anti Viral Drugs Amantadine and rimantadine can be used to prevent influenza A infections. Amantadine blocks the penetration and uncoating of influenza virus particles. Adenine arabinoside or vidarabine disrupts the activity of DNA polymerase and several other enzymes, involved in DNA and RNA synthesis and function. It is given intravenously or applied as an ointment to treat herpes infections . Acyclovir is also used in the treatment of herpes infections . 56

57. Anti Viral Drugs Upon phosphorylation, acyclovir resembles deoxy - GTP and inhibits the virus DNA polymerase. Valacyclovir is an orally administered prodrug form of acyclovir. Ganciclovir , penciclovir , and its oral form famciclovir are effective in treatment of herpesviruses . Foscarnet is an organic analogue of pyrophosphate that binds to the polymerase active site and blocks the cleavage of pyrophosphate from nucleoside triphosphate substrates. 57

58. Anti Viral Drugs It is used in treating herpes and cytomegalovirus infections. Several broad-spectrum anti-DNA virus drugs have been developed . The drug HPMPC or cidofovir , is effective against papovaviruses , adenoviruses, herpesviruses , iridoviruses , and poxviruses. The drug acts on the viral DNA polymerase as a competitive inhibitor and alternative substrate of dCTP . 58

59. Anti Viral Drugs Anti-HIV drugs first drugs to be developed were reverse transcriptase inhibitors such as azidothymidine (AZT) or zidovudine , lamivudine (3TC), didanosine ( ddI ), zalcitabine ( ddC ), and stavudine (d4T ). These interfere with reverse transcriptase activity and therefore block HIV reproduction. HIV protease inhibitors have also been developed . The most used are saquinvir , indinavir , and ritonavir. Protease inhibitors are effective because HIV, like many viruses, translates multiple proteins as a single polypeptide . 59

60. Anti Viral Drugs Polypeptide must then be cleaved into individual proteins required for virus replication . Protease inhibitors mimic the peptide bond that is normally attacked by the protease. The most publicized antiviral agent has been tamiflu . Tamiflu is a neuraminidase Inhibitor . 60

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