BUGS and DRUGS Part 2 March 13, 2013 Marieke Kruidering- Hall

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1 BUGS and DRUGS Part March, 0 Marieke Kruidering- Hall BIOGRAPHY: Marieke Kruidering- Hall is Associate Professor in the Department of Cellular & Molecular Pharmacology. She was born in the Netherlands. She did her undergraduate training in Biopharmaceutical Sciences at Leiden University, where she also did her graduate training in Cellular Toxicology. The focus of her PhD was mechanisms of cisplatin- induced cell death. She joined Dr. Gerard Evan s lab at the Imperial Cancer Research Fund (ICRF) in London to study c myc- induced apoptosis, and continued her postdoctoral studies in this field with him at the UCSF Cancer Center. She participated in the UCSF Postdoctoral Teaching Fellowship Program (PTF) in the spring of 00, facilitating small groups for first- year medical students at UCSF. She joined the faculty of Cellular and Molecular Pharmacology in the fall of 00. Her position at UCSF is dedicated full time to teaching and facilitation of teaching Pharmacology to students in the Schools of Medicine, Pharmacy and Dentistry. She teaches and directs courses in all three schools. In addition, together with her colleagues, Dr. Fulton and Dr. Hyland from the Department of Biochemistry, she directs the PTF program and is active in educational research. She has won numerous teaching awards, is a member of the prestigious Academy of Medical Educators and holds the Academy Chair in Pharmacology Education.

2 Bugs and Drugs: Part. Inhibition of protein synthesis Aminoglycosides, macrolides, tetracyclines, etc.. Inhibition of nucleic acid synthesis Fluoroquinolones, Antifolates, Antiviral agents Marieke Kruidering-Hall, PhD Bacterial DNA Synthesis and Storage DNA Replication requires unwinding Inhibitors of DNA synthesis Fluoroquinolones oxacin Target Gyrase (Topoisomerase II) & Topoisomerase-IV Clinical use Differs by generation, wide spectrum: gram + and - Ranging from UTI, bone infection, pneumonia, skin infections to ANTHRAX Inhibitors of bacterial DNA synthesis in the news FBI investigating anthrax Outbreak Florida Oct. 00 Adverse Drug Reactions GI, dizziness CNS (%), photosensitivity, arthralgia (%), Serious but rare: tendon rupture (<%), arrhythmia (<%) Ciprofloxacin sales increased 0-fold incorrect use increased resistance

3 . Inhibition of protein synthesis. Inhibition of nucleic acid synthesis Fluoroquinolones. Inhibit function of of folic acid Inhibition of folic acid function Sulfonamides and trimethoprim Folic acid plays a key role in the synthesis of the base T in DNA DNA has bases A,C,G,T Inhibitors of folic acid function Enzyme reductase Trimethoprim (TMP) Enzyme synthase Dihydrofolate Tetrahydrofolate Tetrahydrofolate-CH Sulfonamide dtmp Inhibition of folic acid function Sulfonamides and trimethoprim Humans do not have synthase Humans do have reductase TMP inhibits bacterial enzyme more than human enzyme Precursor dump Gertrude Elion: Nobel prize 988 Clinical use of Anti folates Parasites & Bacteria Pneumocystis carinii Toxoplasma gondii Infection Urinary tract infections, Otitis media (ear infection) Respiratory tract infections Adverse drug reactions Allergies ( %) GI disturbances Photosensitivity. Inhibition of protein synthesis. Inhibition of nucleic acid synthesis Fluoroquinolones. Inhibit function of of folic acid. Disruption of cell membrane function

4 Disruption of cell membrane Disruption of fungal cell membrane Lipids in fungal cell membrane differ from human lipids Amphotericin & Nystatin Directly bind to lipid and form HOLES in cell membrane leak causes death of fungus Membrane of fungal cell Disruption of fungal cell membrane Antifungals ALL inhibit ergosterol squalene Clinical Case A -year-old man presented with persistent toenail infection that had not improved with topical azole therapy. Oral therapy was initiated with DNA.Griseofulvin lanosterol. Terbinafine. azoles ergosterol. Amphotericin Clinical Case Oral thrush due to Candida albicans From the CDC Public Health Image Library. Inhibition of protein synthesis. Inhibition of nucleic acid synthesis Antiviral agents, fluoroquinolones. Inhibition of folic acid synthesis. Disruption of cell membrane function

5 Antiviral agents There are far fewer anti-viral drugs than antibacterial drugs. Virus Viral Life cycle Human cell because so much of the viral life cycle is dependent on the machinery of its host. There are many agents that could kill off the virus, but they would kill off host cell as well. So the goal is to find drugs that target molecular machinery unique to the virus.. Fuse. Unpack RNA. RT make DNA. Integrate. Make protein & RNA. Clip protein. Assemble & exit Antiviral agents Antiviral agents THE FLU Drugs Amantadine, Rimantadine Inhibit unpacking neuraminidase Zanamivir (Relenza ) Oseltamivir (Tamiflu ) Inhibit neuraminidase Antibiotics DO NOT WORK against FLU Antiviral agents Human Immunodeficiency Virus HIV Highly Active Antiretroviral Therapy HAART - agents from multiple classes Antiviral agents: HIV Goals of treatment Maximal and durable suppression of HIV viral load Restoration or preservation of immunologic function Reduction of HIV-related morbidity and mortality (disease and death) Minimize long-term complications of therapy (body morphology changes, lipid abnormalities, etc.)

6 Virus Antiviral agents: HIV Human CD + T-cell NRTIs Inhibit DNA production By REVERSE transcriptase. Inhibit DNA production by Reverse Transcriptase AZT. Inhibit protein clipping Protease inhibitors Ritonavir NRTI Resistance = BIG deal NRTI Toxicity protected/mutationtables/pi.shtml Toxicity believed to be associated with inhibition of human Mitochondrial DNA polymerase-gamma: Lactic acidosis Virus Antiviral agents: HIV Human CD + T-cell Protease Inhibitor Toxicity Lipodystrophy syndrome (hyperlipidemia, adipose tissue redistribution), and also insulin resistance. Inhibit DNA production by Reverse Transcriptase AZT. Inhibit protein clipping Protease inhibitors Ritonavir Central obesity Buffalo hump

7 Clinical outcomes HAART Maximal and durable suppression of HIV viral load Restoration or preservation of immunologic function Reduction of HIV-related morbidity and mortality (disease and death) Great progress in drug-formulation Viral resistance to drugs Finding a cure? Challenges. HIV Life cycle & New Drug targets Virus Maraviroc. Fuse. Unpack RNA AZT Human cell In conclusion HIV infection has become a chronic condition that can be managed long term with antiretroviral drugs.. RT make DNA. Integrate Raltegravir. Make protein & RNA. Clip protein Indinavir. Assemble & exit The current drugs do not cure the patient. More research is needed.. Inhibition of protein synthesis. Inhibition of nucleic acid synthesis Antiviral agents, fluoroquinolones. Inhibition of folic acid synthesis. Disruption of cell membrane function In conclusion We discussed how antimicrobial, antiviral & antifungal drugs specifically target the difference between us (humans) and them (microbes). We discussed the concepts of drug resistance and the need for all of us to play an active role in its prevention and delay.

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