OPTO435 Microbiology II Gamal El-Hiti

1. OPTO435 Microbiology II Gamal El-Hiti

2. Antimicrobial Drugs Lecture Two

3. Learning Outcomes OPT435 L02 – W02

4. Antibiotics Chemotherapy is the use a drug (chemical) to treat a disease due to a microbial infection. Antibiotic drugs interfere with the growth of microbes within a host. Antibiotics are of biological origin and produced by microbes to inhibit others. They can be used to treat microbial infections. Chemotherapeutic agents (antibiotics) are synthesized drugs or chemically modified biological products. OPT435 L02 – W02

5. Antibiotics  Why is it more difficult to treat Gram-negative bacteria in comparison to Gram-positive bacteria?  Resistance against antibiotics is more common in Gram-negative bacteria due to the presence of external membrane covering the cell wall, but this membrane is absent in Gram-positive bacteria.  Gram-negative bacteria have channels that can prevent the entry of antibiotics.  Also, the channels can expel out antibiotics. OPT435 L02 – W02

6. Antibiotics  Gram-positive bacteria produce exotoxins, but Gram-negative bacteria produce exotoxins and endotoxins. OPT435 L02 – W02

7. Antibiotics OPT435 L02 – W02

8. History of Antibiotics  Salvarsan (arsphenamine) was synthesized by Paul Ehrlich in 1907 and was introduced by Sahachiro Hata as the first effective treatment of syphilis in 1910.  The concept of chemotherapy to treat microbial diseases was born.  Fleming discovered penicillin in 1928.  Sulfa drugs (sulfanilamide) were discovered in 1932 against Gram + bacteria.  Howard Florey and Ernst Chain performed the first clinical trial of penicillin in 1940. OPT435 L02 – W02

9. History of Antibiotics  Selective toxicity  Antimicrobial drugs are chemicals that have selective toxicity against microbes without damaging the host cells.  Therapeutic index  The ratio between the toxic dose and the therapeutic dose or ratio of the median lethal dose (LD50) to median effective dose (ED50).  LD50 is the quantity of a drug that kills 50% of the test sample. OPT435 L02 – W02

10. Antibiotics Mode of Action  ED50is the dose that produces the desired effect within 50% of a population.  High therapeutic index means less toxic.  Antibiotics action  Different antibiotics have different mode of action depending on their structures and degree of affinity to certain target sites within the bacterial cells. Inhibitors for cell wall synthesis Humans and animals cells do not have cell walls. OPT435 L02 – W02

11. Antibiotics Mode of Action A drug that targets cell walls can selectively kill or inhibit bacterial organisms. Inhibitors for cell membrane function Cell membranes are important barriers that regulate the flow of substances. Membranes disruption could result in leakage of solutes needed for cell’s survival. Inhibitors for protein synthesis Enzymes are primarily made of proteins. Protein is necessary for the multiplication of all bacterial cells. OPT435 L02 – W02

12. Antibiotics Mode of Action Several types of antibacterial agents bind to either 30S or 50S subunits of ribosomes. This activity leads to death of organism. Inhibitors for nucleic acid synthesis DNA and RNA are keys to the replication. Some antibiotics compromise bacterial multiplication and survival. Inhibitors for other metabolic processes e.g.Disruption of folic acid pathway, which is a necessary step for bacteria to produce precursors for DNA synthesis. OPT435 L02 – W02

13. Penicillin (-lactams) OPT435 L02 – W02

14. Penicillin (-lactams) OPT435 L02 – W02

15. Penicillin (-lactams)  Penicillin is a group of antibiotics.  Natural and semisynthetic penicillins contain β-lactam ring.  Natural penicillins produced by Penicilliumare effective against Gram positive cocci and spirochetes.  Semisynthetic penicillins can be made in laboratory by adding different side chains into the β-lactam ring.  Penicillins are still widely used today, but many bacteria have now become resistant. OPT435 L02 – W02

16. Penicillin (-lactams)  Bacteria that attempt to grow and divide in the presence of penicillin fail to do so.  Bacteria end up shedding their cell walls. OPT435 L02 – W02

17. Penicillin (-lactams)  Bacteria are constantly remodel their peptidoglycan cell walls.  They build and break down portions of the cell wall as they grow and divide.  β-Lactam antibiotics inhibit the formation of peptidoglycan cross-links by binding to the enzyme DD-transpeptidase.  As a consequence, DD-transpeptidase cannot catalyse formation of these cross-links, causing the cell to rapidly die.  If you are allergic to penicillin, tell the doctor. OPT435 L02 – W02

18. Penicillin (-lactams) OPT435 L02 – W02

19. Penicillin (-lactams)  Penicillinase (β-lactamase)  Bacterial enzyme that destroys natural penicillins.  Penicillinase resistant penicillins  Methicillin replaced by oxacillin and nafcillin due to methicillin-resistant Staphylococcus aureus (MRSA).  Extended-spectrum penicillins  Ampicillin, amoxicillin, carboxypenicillins and ureidopenicillins (also good against Pseudomonas aeruginosa). OPT435 L02 – W02

20. Penicillin (-lactams) OPT435 L02 – W02

21. Cephalosporins (-lactams)  The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium.  More stable to bacterial β-lactamases than penicillin.  Broader spectrum to be used against penicillin-resistant strains.  Structure and mode of action resembles penicillin. OPT435 L02 – W02

22. Vancomycin (glycopeptides)  Vancomycin recognizes and binds to the two D-ala residues on the end of the peptide chains. However, in resistant bacteria, the last D-ala residue has been replaced by a D-lactate, so vancomycin cannot bind. OPT435 L02 – W02

23. Vancomycin (glycopeptides) •  Used to kill Methicillin-resistantStaphylococcus aureus (MRSA) which is a bacterium responsible for several difficult-to-treat infections in humans. •  Inhibition of cell wall synthesis. OPT435 L02 – W02

24. Other Antibiotics OPT435 L02 – W02

25. Antibiotics and Normal Flora •  Antibiotics act only against bacteria and are ineffective against viral infections caused by viruses. •  Research on antibiotics showed that taking even a single regimen of antibiotics (i.e. about 10 days) makes a person 3 to 4 times more likely to get another infection. •  This is because antibiotics often kill off too many of the host’s inherent beneficial flora leaving the host even more unprotected against new infectious agents. OPT435 L02 – W02

26. Kirby-Bauer Test  Kirby-Bauer antibiotic testing  It is a disk diffusion antibiotic sensitivity testing.  It is a test which uses antibiotic-impregnated wafers to test whether particular bacteria are susceptible to specific antibiotics.  White wafers containingantibiotics are placed on aplate of bacteria. OPT435 L02 – W02

27. Kirby-Bauer Test  Circles of poor bacterial growth surround some wafers indicating susceptibility to the antibiotic. OPT435 L02 – W02

28. Antibiotic Resistance •  Bacteria can develop resistance to antibiotics by mutating existing genes, or by acquiring new genes from other strains. •  A variety of mutations can lead to antibiotic resistance. •  Mechanisms of antibiotic resistance •  Enzymatic destruction of drug •  Prevention of penetration of drug •  Alteration of drug's target site •  Rapid ejection of the drug OPT435 L02 – W02

29. Antibiotic Resistance OPT435 L02 – W02

30. Antibiotic Resistance •  Misuse of antibiotics selects for resistance mutants. •  Misuse of antibiotics includes one or more of the following: •  Using outdated or weakened antibiotics. •  Using antibiotics for the common cold and other inappropriate conditions. •  Using antibiotics in animal feed. •  Failing to complete the prescribed regimen. •  Using someone else's leftover prescription. OPT435 L02 – W02

31. Antibiotic Resistance OPT435 L02 – W02

32. Antifungal Drugs •  Antifungal is a pharmaceutical fungicide used to treat mycoses such as athlete's foot and ringworm. •  Polyene antifungals •  It has multiple conjugated double bonds. OPT435 L02 – W02

33. Antifungal Drugs •  Polyene antifungals •  It bind with sterols in the fungal cell membrane (Inhibition of ergosterol). OPT435 L02 – W02

34. Antiparasitic Drugs •  Antiparasitics are medications that can be used to treat parasitic diseases. •  The empiric use of cinchona-bark to treat parasitic diseases began in the 17th century. •  The isolation of the alkaloid quinine was isolated in 1820. •  Early antiparasitics were ineffective, frequently toxic to patients and difficult to administer due to the difficultyin distinguishing between host and parasite. OPT435 L02 – W02

35. Antiparasitic Drugs •  Diethylcarbamazine is used in the treatment of certain worm infections. •  This medicine works by killing the worms. •  It can not kill pinworms or tapeworms. •  It is not expected that diethylcarbamazine will cause different side effects or problems in children than it does in adults. OPT435 L02 – W02

36. AntiviralDrugs •  Antiviral drugs are a class of medication that used specifically for treating viral infections caused by viruses. •  Like antibiotics specific antivirals are used for specific viruses. •  Unlike most antibiotics, antiviral drugs can not destroy their target pathogen without destroying the host cells. •  They inhibit the viruses development. •  Highly active antiretroviral therapies HAART) is used to treat virial infections. OPT435 L02 – W02

37. AntiviralDrugs •  Designing safe and effective antiviral drugs is difficult, because viruses use the host's cells to replicate. •  This makes it difficult to find targets for the drug that would interfere with the virus cells without harming the host organism's cells. •  Moreover, the major difficulty in the development and manufacture of vaccines and new antiviral drugs is due to the viral variation. OPT435 L02 – W02

38. AntiviralDrugs  Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are antiretroviral drugs used in the treatment of human immunodeficiency virus (HIV).  NNRTIs inhibit reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of HIV.  RT is one of the most popular targets in the field of antiretroviral drug development.  Some progress has been made with NNRTIs. OPT435 L02 – W02

39. AntiviralDrugs  Acyclovir  Is a guanosine analogue antiviral drug.  Ii inhibits DNA synthesis.  Inhibition of herpes virus replication and treatment of chickenpox and shingles.  OPT435 L02 – W02

40. AntiviralDrugs OPT435 L02 – W02