Antibacterial Therapeutics

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Lecture on Antibacterial Drugs used in medicine

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Antibacterial Therapeutics:

Antibacterial Therapeutics Varun C N

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Antibacterial Therapeutics 2

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Antibacterial Therapeutics 3 Cell Wall Synthesis Inhibitors Penicillins Cephalosporins Vancomycin Carbapenems Aztreonam Polymycin Bacitracin Protein Synthesis Inhibitors Inhibit 30s Subunit Aminoglycosides (gentamycin) Tetracyclines Inhibit 50s Subunit Macrolides Chloramphenicol Clindamycin Linezolid Streptogramins Some common examples

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Antibacterial Therapeutics 4 DNA Synthesis Inhibitors Fluoroquinolones Metronidazole Folic Acid synthesis inhibitors Sulfonamides Trimethoprim RNA synthesis Inhibitors Rifampin

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Antibacterial Therapeutics 5

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Antibacterial Therapeutics 6 Beta lactam Drugs

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Antibacterial Therapeutics 7 Martin Thanbichler & Lucy Shapiro Nature Reviews Microbiology 6, 28-40 (January 2008)

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Antibacterial Therapeutics 8

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Antibacterial Therapeutics 9 Penicillin Amoxicillin Ampicillin Bacampicillin Carbenicillin Cloxacillin Dicloxacillin Flucloxacillin Mezlocillin Nafcillin Oxacillin Penicillin G Penicillin V Piperacillin Pivampicillin Pivmecillinam Ticarcillin

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Antibacterial Therapeutics 10 Daryl D. DePestel J Am Pharm Assoc. 2008;48(4):530-540.

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Antibacterial Therapeutics 11 First generation Are moderate spectrum agents. Effective for treating staphylococcal and streptococcal infections and for skin and soft-tissue infections, as well as for streptococcal pharyngitis. Have activity against some Escherichia coli , Klebsiella pneumoniae and Proteus mirabilis Second generation Have a greater gram-negative spectrum More resistant to beta-lactamase Useful agents for treating upper and lower respiratory tract infections, sinusitis and otitis media Cefoxitin is a second generation cephalosporin with anaerobic activity.

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Antibacterial Therapeutics 12 Third generation Have a broad spectrum of activity and increased activity against gram-negative organisms. Have excellent activity against most strains of streptococcus pneumoniae. Have activity against Neisseria gonorrhoeae . Fourth generation Have a greater resistance to beta-lactamases than the third generation cephalosporins . Can cross blood brain barrier and are effective in meningitis. Cefpirome is more active against pneumococci. Activity against nosocomial pathogens such as Enterobacter and Acinetobacter .

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Antibacterial Therapeutics 13 Carbapenems Bactericidal antibiotic Active against gram-positive and gram-negative aerobic and anaerobic pathogenic bacteria. Resist the hydrolysis by most beta-lactamases Imipenem Meropenem Doripenem Ertapenem

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Antibacterial Therapeutics 14 Glycopeptide antibiotics of the vancomycin family Huawei Chen,  PNAS; 11942–11947

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Antibacterial Therapeutics 15 Beta lactamase inhibitors

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Antibacterial Therapeutics 16

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Antibacterial Therapeutics 17 Drawz SM, Bonomo RA Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010 Jan;23(1):160-201.

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Antibacterial Therapeutics 18 Aminoglycosides Amikacin Gentamicin Kanamycin Neomycin Netilmicin Paromomycin Streptomycin Tobramycin

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Antibacterial Therapeutics 19 Puglisi etal The EMBO Journal (1999) 18 , 3133 - 3138

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Antibacterial Therapeutics 20 Macrolides Azithromycin Erythromycin Clarithromycin Dirithromycin Roxithromycin Telithromycin

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Antibacterial Therapeutics 21 http://www.weizmann.ac.il/sb/faculty_pages/Yonath/00Sc_activities.html

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Antibacterial Therapeutics 22 Sally Rafie Pharmacotherapy. 2010;30(3):290-303

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Antibacterial Therapeutics 23 Sulfonamides Sulfamethizole Sulfamethoxazole Sulfisoxazole Trimethoprim - Sulfamethoxazole ( Co- trimoxazole )

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Antibacterial Therapeutics 24

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Antibacterial Therapeutics 25 Tetracycline group Demeclocycline Doxycycline Minocycline Oxytetracycline Tetracycline Tigecycline ( Glycylcyclines ) Core structure

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Antibacterial Therapeutics 26 V. Ramakrishnan Cell, Volume 103, Issue 7, 1143-1154, 22 Overview of Tetracycline, Pactamycin, and Hygromycin B in the 30S SubunitAntibiotics are shown as space-filling models, with tetracycline (blue), pactamycin (green), and hygromycin B (red). The parts of 16S RNA that make contacts with any of the three antibiotics are colored as in the following figures.

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Antibacterial Therapeutics 27

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Antibacterial Therapeutics 28 Quinolones and fluoroquinolones Basic chemical structure of fluoroquinolones

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Antibacterial Therapeutics 29 Flumequine Nalidixic acid Oxolinic acid Piromidic acid Pipemidic acid Rosoxacin First generation Ciprofloxacin Enoxacin Lomefloxacin Nadifloxacin Norfloxacin Ofloxacin Pefloxacin Rufloxacin Second Generation Third Generation Balofloxacin Gatifloxacin Grepafloxacin Levofloxacin Moxifloxacin Pazufloxacin Sparfloxacin Temafloxacin Tosufloxacin Besifloxacin Clinafloxacin Gemifloxacin Sitafloxacin Trovafloxacin Prulifloxacin Fourth Generation

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Antibacterial Therapeutics 30 Bossche etal Journal of Pharmaceutical and Biomedical Analysis Volume 22, Issue 5, June 2000, Pages 763–772

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Antibacterial Therapeutics 31 Quinolones and fluoroquinolones are bactericidal drugs, actively killing bacteria. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription David T. Bearden, Pharmacotherapy. 2001;21(10s)

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Antibacterial Therapeutics 32 Streptogramins The molecular target of streptogramins is the 23S rRNA. Both streptogramin A and B bind to the P binding site of the 50S ribosome subunit. The type A streptogramin binding causes a conformational change to the 50S subunit, which increases the activity of the type B by a 100-fold. Streptogramin B prevents the elongation of protein chains and causes the release of incomplete peptides

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Antibacterial Therapeutics 33 Group A antibiotics contain a 23-membered unsaturated ring with lactone and peptide bonds Group B antibiotics are depsipeptides (lactone-cyclized peptides) Group A Group B Source: Wikipedia

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Antibacterial Therapeutics 34 Madumycin II

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Antibacterial Therapeutics 35 Pristinamycin Pristinamycin IA+ Pristinamycin IIA Pristinamycin IA (Macrolide) Pristinamycin IIA (Streptogramin A)

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Antibacterial Therapeutics 36 Lincomycin Clindamycin Lincomycin group Clindamycin's mechanism of action resembles that of the macrolides

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Antibacterial Therapeutics 37 Anti- Mycobacterium drugs Isoniazid Ethambutol Rifamycin Pyrazinamide

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Antibacterial Therapeutics 38 Isoniazid

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Antibacterial Therapeutics 39 Douglas B. Young Current Biology Volume 4, Issue 4, 1 April 1994, Pages 351–353

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Antibacterial Therapeutics 40 Chemical structure of pyridomycin Towards a new tuberculosis drug: pyridomycin – nature’s isoniazid Cole etal. EMBO Mol Med (2012) 4, 1032–1042 NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA is the principal target andpyridomycin inhibits mycolic acid synthesis in M. tuberculosis.

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Antibacterial Therapeutics 41 Ethambutol Ethambutol inhibits RNA synthesis and decreases tubercle bacilli replication. Nearly all strains of M. tuberculosis and M. kansasii as well as a number of strains of MAC are sensitive to ethambutol. Ethambutol inhibits arabinosyl transferases involved in cell wall biosynthesis

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Antibacterial Therapeutics 42 William R. Jacobs Jr Antimicrob. Agents Chemother. February 2005 vol. 49 no. 2 708-720

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Antibacterial Therapeutics 43 Rifamycins By binding next to RNA polymerase's active center (pink), the potent class of antibiotics called rifamycins (red and yellow) prevents bacterial RNA from elongating. 1. http://www.sciencedaily.com/releases/2008/08/080825110423.htm 2. Nature Biotechnology 26, 1250 (2008). doi:10.1038/nbt1108-1250 1. 2.

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Antibacterial Therapeutics 44 New target for inhibition of bacterial RNA polymerase: “switch region” Ebright etal. Current Opinion in Microbiology.2011;14(5), 532–543

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Antibacterial Therapeutics 45 P.A. Aristoff et al. Tuberculosis . 90 (2010) . 94e118

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Antibacterial Therapeutics 46 Pyrazinamide It kills a population of semi-dormant tubercle bacilli in acidic pH environments that are not killed by other TB drugs Pyrazinamide is only active against M. tuberculosis at acid pH , an environment that is produced during active inflammation, and its activity is closely related to the acidity of the medium.

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Antibacterial Therapeutics 47 Pyrazinamide Pyrazinoic acid Disrupts membrane energetics and inhibits membrane transport function Mary Margaret Wade And Ying Zhang Mechanisms Of Drug Resistance In Mycobacterium Tuberculosis Frontiers in Bioscience 9, 975-994, January 1, 2004

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Antibacterial Therapeutics 48 Simi S Paknikar and Sarala Narayana N Am J Med Sci. 2012 November; 4(11): 537–547

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Antibacterial Therapeutics 49 New approaches

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Antibacterial Therapeutics 50 Bactibase database Halocin-C8 Produced by: Halobacterium sp (strain AS7092) Mode of action: Causes cell lysis and death, possibly by disrupting the cell wall.

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Antibacterial Therapeutics 51 Phage therapy Vincent A Fischetti, Daniel Nelson & Raymond Schuch Nature Biotechnology 24, 1508 - 1511 (2006)

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Antibacterial Therapeutics 52

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