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BUGS and DRUGS Part 1 March 6, 2013 Marieke KruideringHall BIOGRAPHY: Marieke KruideringHall 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 cisplatininduced cell death. She joined Dr. Gerard Evan’s lab at the Imperial Cancer Research Fund (ICRF) in London to study c mycinduced 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 2002, facilitating small groups for firstyear medical students at UCSF. She joined the faculty of Cellular and Molecular Pharmacology in the fall of 2002. 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.

Transcript of BUGS and DRUGS-biominimedicalschool.ucsf.edu/syllabus/winter2013/Inside/3-6 - Bugs... · University...

Page 1: BUGS and DRUGS-biominimedicalschool.ucsf.edu/syllabus/winter2013/Inside/3-6 - Bugs... · University of California San Francisco Medical School Bugs and Drugs: Part 1 Marieke Kruidering-Hall,

 

BUGS  and  DRUGS    Part  1  

March  6,  2013  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  2002,  facilitating  small  groups  for  first-­‐year  medical  students  at  UCSF.    She  joined  the  faculty  of  Cellular  and  Molecular  Pharmacology  in  the  fall  of  2002.  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.    

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University of California San Francisco Medical School

Bugs and Drugs: Part 1

Marieke Kruidering-Hall, PhD

University of California San Francisco Medical School

•  We need an immune system to live

•  The immune system is complex and awesome

•  We have tons of bacteria on our skin and in our gut

•  Bug names: Anthrax, E. coli, pneumococcus, H. influenza, Staph. aureus (video of neutrophil chasing the Staph. aureus)

Last week……you learned

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•  Sometimes the immune system has trouble: We met Elizabeth !

Last week……you learned

•  CVID: Problem making antibodies

•  T cells (lymphocytes) HIV infection

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The question is

Did your immune system ever have trouble ?

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How antimicrobial drugs work

Questions we will address 1.  How do antimicrobial drugs work ? 2.  Why do antibiotics give you diarrhea ? 3.  Why do you always have to finish a prescription? 4.  Why was Elizabeth sometimes not helped

completely by antibiotics ?

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How antimicrobial drugs work

Microorganisms 1.  Bacteria 2.  Fungi 3.  Protozoa 4.  Helminths 5.  Viruses

Differ from human eukaryotic cells

Drugs target these differences: affect microbe without affecting host

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Overview of Drug Targets 1. Inhibition of cell wall synthesis

Penicillins, cephalosporins, vancomycin 2. Inhibition of protein synthesis

Aminoglycosides, macrolides, tetracyclines

3. Inhibition of nucleic acid synthesis Antiviral agents, fluoroquinolones

4. Inhibition of folic acid synthesis Sulfonamides, trimethoprim

5. Disruption of cell membrane function Antifungal agents

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How to pick the correct antimicrobial drug? Identity of infecting organism & its drug susceptibility

Minimal Inhibitory Concentration (MIC): Lowest concentration of an antimicrobial agent that inhibits the growth of an organism isolated from a patient. Determined by tube dilution of disc diffusion assay

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How to pick the correct antimicrobial drug? Identity of infecting organism & its drug susceptibility

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Fate of a microbe facing “Drug A”

Drug

A

Our defense kills remaining microbes

Happy patient

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Antibiotics rely on your immune system to finish the

job ….

Drug A

Our defense kills microbe, if

numbers are low

Happy patient

Can u explain why Elizabeth sometimes was not helped by antibiotics?

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How antimicrobial drugs work

Questions we will address 1.  How do antimicrobial drugs work ? 2.  Why do antibiotics give you diarrhea ? 3.  Why do you always have to finish a prescription? 4.  Why was Elizabeth sometimes not helped

completely by antibiotics ?

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Drug Resistance by “selection”

Drug

A

Different drug

needed

Drug A stopped too soon Our defense cannot kill high number of microbes !

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How to pick the correct antimicrobial drug? Identity of infecting organism & its drug susceptibility Bacterial or bacteriostatic drug?

•  Severity of illness •  History of drug allergies (NKA) •  Patient age •  Pregnancy

Patient:

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Everywhere I go people want to thank me for saving their lives. I really don't know why... . Nature created penicillin, I only found it. ���- Alexander Fleming, c. 1955

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Prokaryote has CELL WALL

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Inhibitors of cell wall synthesis Penicillins, cephalosporins, vancomycin

Outside

Inside

peptidoglycan

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Courtesy of Gary Kaiser

Transpeptidases Crosslinks chains

Inhibitors of cell wall synthesis Penicillins, cephalosporins, vancomycin

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Bactericidal 1. Bind to penicillin binding proteins (PBPs) 2. Inhibit transpeptidation: “cross-link” 3. Activate autolytic enzymes: bactericidal

Inhibitors of cell wall synthesis Penicillins, cephalosporins, vancomycin

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Penicilin in Action

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•  Beta-lactam ring structure required •  Resistance through “beta lactamases”

Inhibitors of cell wall synthesis Penicillins, cephalosporins, vancomycin

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Resistance to Penicillins

I.  Formation of beta-lactamases

chewing up the beta-lactam ring

II.  Changed PBPs

preventing antibiotic binding III. Changed porin structure

preventing access of antibiotic

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1. Skin & soft tissue infections (Staphylococci)

2. Throat & skin infections (Streptococci)

3. Meningitis, gonorrhea, syphilis (Neisseria g & N. meningitidis,T pallidum)

Fleming with Anne Schaefe Miller, the first patient whose life was saved with penicillin, 1942.

Inhibitors of cell wall synthesis Clinical use of Penicillins

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Adverse drug reactions: I. Opportunistic Infections (dose dependent) Suppression of normal “flora” allows “overgrowth”

Oral/vaginal candidiasis Diarrhea Bacterial colitis (C. difficile)

II. True allergy to Penicillins (5 % of population) Degradation products of beta-lactams are “antigenic”. rash*, swelling, itching

anaphylaxis (occurs fast: within minutes to 4 hrs)

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Adverse Drug Reactions PCNs: True allergy to Penicillins is not an ampicillin rash

maculopapular rash – ampicillin

Rash is not life-threatening PCN use can be safe (test)

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Inhibitors of cell wall synthesis Penicillins Cephalosporins Vancomycin

PCN, cephs

Vanco

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Inhibitors of cell wall synthesis: Historical perspective

S. aureus 1940

PCN Penicillin resistant S. aureus

1950s 1959

Methicillin

Methicillin resistant S. aureus (MRSA) 1960 -1970s

Vancomycin

Vancomycin resistant S. aureus (VRSA) 2002

Daptomycin, linezolid, quinupristin-dalfopristin

? Clin. Infect. Dis. 42 179-180, 2006

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02

46

810

1214

16

Depres. Anxiety Bladder Osteopor Antibact ErectDys Obesity

Number of New Molecular Entities (NMEs) submitted to FDA by world’s 15 largest pharmaceutical companies

Pharmaceutical Industry

(Clin Infect Dis 2004; 38: 1279-86)

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Methicillin resistant S. aureus

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Overview of Drug Targets

1. Inhibition of cell wall synthesis Penicillins, cephalosporins, vancomycin

2. Inhibition of protein synthesis Aminoglycosides, macrolides, tetracyclines

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Inhibition of protein synthesis Aminoglycosides, macrolides, tetracyclines

1.  Single strand copy of DNA

2.  RNA modified to mRNA

3.  mRNA travels out of nucleus

4.  Ribosomes make protein based on mRNA

5.  Ribosomes differ between bacteria and humans!!

eukaryote University of California San Francisco Medical School

Inhibitors of protein synthesis

Selman Abraham Waksman, Rutgers University

Nobel Prize 1952 "for his discovery of streptomycin, the first antibiotic effective against tuberculosis”

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Inhibitors of protein synthesis

Aminoglycosides (IV) Streptomycin, gentamicin, tobramycin, amikacin and neomycin* Use: Tuberculosis, plague, endocarditis Adverse drug reactions: GI upset Nephrotoxicity(6 %) Ototoxicity Vestibular dysfunction (0.5 %)

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Inhibitors of protein synthesis

Macrolides Erythromycin, clarithromycin, azithromycin Use: Respiratory tract infections, chlamydia, Bordetella Adverse drug reactions GI upset

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Inhibitors of protein synthesis Tetracyclines

Doxycycline, tetracycline

Use: Community acquired pneumonia (CAP) Chlamydia, cholera, H. Pylori, acne Adverse Drug reactions GI upset Tooth discoloration Photosensitivity

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Inhibitors of protein synthesis Tetracycline and tooth discoloration

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Summary

1. Inhibition of cell wall synthesis Penicillin, cephalosporin, vancomycin

2. Inhibition of protein synthesis Aminoglycosides, macrolides, tetracyclines

1.  How do antimicrobial drugs work ? 2.  Why do antibiotics give you diarrhea ? 3.  Why do you always have to finish a prescription? 4.  Why was Elizabeth sometimes not helped

completely by antibiotics ?