Vancomycin

1. Vancomycin Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with sugar residues attached to it.

2. Vancomycin Mechanism of Action • Bacterial Cell Wall Synthesis (review) • http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/ppgsynanim.html • http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/vanres.html Penicillin Mechanism of Action (review) http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/penres.html

3. Mechanism of Action of Vancomycin Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin. Thus, the peptidoglycan subunit is appropriately incorporated into the cell wall.

4. Vancomycin Uses • Vancomycin is used to treat aerobic Gram + bacteria, including MRSA and strains of penicillin-resistant Streptococcus pneumoniae • Vancomycin is administered intraveneously • Vancomycin can also be used to treat anearobic Gram + bacteria, including Clostridium difficile (in the case of a GI infection, Vancomycin can be administered orally). • Vancomycin cannot be used to treat Gram – bacteria, since the large size of the vancomycin molecule prohibits its passing of the outer membrane.

5. Vancomycin Resistance • Some Enterococci have developed resistance to vancomycin (Enterococcus faecium and Enterococcus faecalis). • These bacteria are called Vancomycin Resistant Enterococci (VRE)

6. The mechanism of resistance involves the transformation of the D-Ala-D-Ala linkage in the peptide side chain into D-Ala-D-Lac (i.e. replacement of the NH2 group by an OH group) • This terminal linkage is still recognized by the essential PBP’s (so the cell wall can still be constructed), but is not recognized by vancomycin (thus resulting in resistance).

7. Antimicrobial Activity of Vancomycin

8. Daptomycin • Daptomycin is called a lipopeptide antibiotic • Approved for use in 2003 • Lipid portion inserts into the bacterial cytoplasmic membrane where it forms an ion-conducting channel. • Marketed under the trade name Cubicin

9. Step 1: Daptomycin binds to the cytoplasmic membrane in a calcium-dependent manner Step 2: Daptomycin oligomerizes, disrupting the membrane Step 3: The release of intracellular ions and rapid death

10. Uses of Daptomycin • Daptomycin is active against many aerobic Gram-positive bacteria • Includes activity against MRSA, penicillin-resistant Streptococcus pneumoniae, and some vancomycin-resistant Enterococci (VRE) • Daptomycin is not active against Gram negative strains, since it cannot penetrate the outer membrane.

11. Primarily been used to treat skin and soft tissue infections • Poor activity in the lung.

12. Antimicrobial Activity of Daptomycin

13. Rifamycins • Rifampin is the oldest and most widely used of the rifamycins • Rifampin is also the most potent inducer of the cytochrome P450 system

14. Therefore, Rifabutin (brand name Mycobutin) is favored over rifampin in individuals who are simultaneously being treated for tuberculosis and HIV infection, since it will not result in oxidation of the antiviral drugs the patient is taking

15. Rifaximin is a poorly absorbed rifamycin that is used for treatment of travelers’ diarrhea.

16. Mechanism of Action of Rifampin • Rifampin inhibits transcription by inactivating bacterial RNA polymerase

17. Resistance develops relatively easily, and can result from one of a number of single mutations in the baqcterial gene that encodes RNA polymerase. • Therefore, Rifampin is rarely used as monotherapy (i.e. not used as a single agent) but usually combined with other antibiotics

18. Uses of Rifampin • Used, in combination with other drugs, to treat Mycobacterium tuberculosis • Used to treat some Staphylococcal infections.

19. The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which can be administered orally. Rifampin can also be administered parenterally.

20. Aminoglycosides The structure of the aminoglycoside amikacin. Features of aminoglycosides include amino sugars bound by glycosidic linkages to a relatively conserved six-membered ring that itself contains amino group substituents.

21. Aminoglycoside Mechanism of Action • Aminoglycosides bind to the 30S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis (translation) • http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html • http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

22. Uses of Aminoglycoside Antibiotics • Unlike vancomycin, the aminoglycosides have excellent activity against Gram – aerobic bacteria • Their extensive positive charge enables them to bind to and penetrate the negatively charged outer membrane and get into the periplasm • They are further transported into the cytoplasm by a bacterial transport system.

23. Lipopolysaccharide is Part of the Outer Membrane of Gram Negative Bacteria

26. Bacterial lipopolysaccharides are toxic to animals. When injected in small amounts LPS or endotoxin activates several host responses that lead to fever, inflammation and shock.

27. Endotoxins may play a role in infection by any Gram-negative bacterium. The toxic component of endotoxin (LPS) is Lipid A. The O-specific polysaccharide may provide for adherence or resistance to phagocytosis, in the same manner as fimbriae and capsules.

28. The O polysaccharide (also referred to as the O antigen) also accounts for multiple antigenic types (serotypes) among Gram-negative bacterial pathogens. • Thus, E. coli O157 (the Jack-in-the-Box and Stock Pavillion E. coli) is #157 of the different antigenic types of E. coli and may be identified on this basis.

29. Bacterial resistance to aminoglycosides occurs via one of three mechanisms that prevent the normal binding of the antibiotic to its ribosomal target: • Efflux pumps prevent accumulation of the aminoglycoside in the cytosol of the bacterium. • Modification of the aminoglycoside prevents binding to the ribosome. • Mutations within the ribosome prevent aminoglycoside binding.

30. The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral).

31. The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral).

32. Macrolides and Ketolides The structures of erythromycin and telithromycin Circled substituents and distinguish telithromycin from the macrolides.

33. Substituent allows telithromycin to bind to a second site on the bacterial ribosome.

35. Mechanism of Action of Macrolide Antibiotics • Macrolides bind tightly to the 50S subunit of the bacterial ribosome, thus blocking the exit of the newly synthesized peptide • Thus, they are interfering with bacterial translation • http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html • http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/kaiser/mechanisms/altribo_antibiot.html

36. Uses of Macrolide Antibiotics • Active against a broad range of bacteria • Effective against some stphylococci and streptococci, but not usually used for MRSA or penicillin-resistant streptococci • Most aerobic Gram- bacteria are resistant • Active against many atypical bacteria and some mycobacteria and spirochetes

37. The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally).

38. Uses of Telithromycin (a ketolide) • Telithromycin is approved for use against bacterial respiratory infections • Active against most strains of Streptococcus pneumoniae, including penicillin- and macrolide-resistant strains • Also active against more strains of Staphylococci • Only available in oral formulation

39. The related ketolide class consists of Telithromycin (oral).

40. The Tetracycline Antibiotics The structure of tetracycline

41. Tetracycline Antibiotics Tetracycline Tigecycline Doxycycline

42. Mechanism of Action of the Tetracycline Antibiotics • The tetracyclines bind to the 30S subunit of the bacterial ribosome and prevent binding by tRNA molecules loaded with amino acids. • http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/tetres.html

43. Uses of the Tetracycline Antibiotics • Main use is against atypical bacteria, including reckettsiae, chlamydiae, and mycoplasmas • Also active agains some aerobic Gram-positive pathogens and some aerobic Gram-negative bacteria

44. The Tetracycline Class of Antibiotics consists of Doxycycline and Tigecycline (parenteral) as well as Tetracycline, Doxycycline and Minocycline (oral)

45. Tigecycline

46. The antimicrobial activity of Tigecycline (parenteral)

47. Chloramphenicol

48. Mechanism of Action of Chloroamphenicol • Binds to the 50S subunit of the bacterial ribosome, where it blocks binding of tRNA

49. Uses of Chloramphenicol • Severe toxicity limits utility • The most serious side effect of chloramphenicol treatment is aplastic anaemia (a condition where bone marrow does not produce sufficient new cells to replenish blood cells) • This effect is rare and is generally fatal: there is no treatment and there is no way of predicting who may or may not get this side effect. • The effect usually occurs weeks or months after chloramphenicol treatment has been stopped.

50. Uses of Chloramphenicol • However, despite its toxicity, chloramphenicol has a wide spectrum of activity, that includes many aerobic Gram-positive, Gram-negative, anaerobic, and atypical bacteria