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Summary Lectures Antimicrobial Compounds

Name: Lectures Antimicrobial Compounds
SKU: doc_914580
Rating: 4.00 (4 reviews)
Author: vustudent98

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Vrije Universiteit Amsterdam (VU)

All lectures of the course Antimicrobial Compounds of the Minor "Topics in Biomedical Sciences" This is the most extensive summary out there, my absolute life and soul are in this document. Everything that has been discussed in the lectures is in there. Studying this, you should not be able to fai...

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2 items

1. Samenvatting - Lectures antimicrobial compounds
2. Samenvatting - Innovative cell biology and immunology - summary of all lectures
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LECTURES – PART 1
1.1 – HISTORY OF ANTIBIOTICS
ANTIMICROBIALS
Importance of antimicrobials
= One of most successful medications ever discovered
1) Huge benefit for patient
2) Low toxicity
3) Low costs
- Reduction surgical wound infection 40% → 2%
- Antibiotics increased average life span with 10 years
o In perspective: Curing cancer would increase average lifespan by 3 years
- Antimicrobials: compounds active against
1) Bacteria
2) Viruses
3) Protozoa
4) Yeasts and fungi
5) Worms

FIRST ANTIBIOTICS
SALVARSAN
Paul Ehrlich (1854-1915)
- “To achieve success in antimicrobial research, one needs the four G’s: Geld, Geduld, Geschick
and Gluck – money, patience, intelligence and luck.”
- Trained as a chemist
- 1908: Nobel prize
- Development and testing different staining techniques for blood cells
o Discovery of mast cells – staining of specifically mast cells
→ Development idea of specific receptor for stains: something in the cells specific for binding
to a dye → “If tissues and cells can be specifically targeted by dyes, they might also be
specifically targeted by toxic dyes”
- Therapia Sterilisans Magna – Magic Bullet: Discover a treatment that could, in a single dose,
destroy all microorganisms in the infected organism
o To achieve this, the optimal agents would combine high parasitotropism with low
organotropism
- Discovery of Salvarsan
1. Focus on arsenic derivatives → combination: basic dye + aniline +
toxin (arsenic acid)
→ Arsanilic acid
§ Active
§ Highly toxic
2. Modification of amino group
→ Arsacetin
§ Less toxic
§ Activity in vivo
§ No activity in vitro
→ Hypothesis: compounds activated in vivo by modification
• Now known modification = reduction
3. Focus on arsenobenzenes → reduction toxicity
→ Arsanenophenylglycine

, → Arsenophenol
§ Difficult to produce
§ Prone to oxidation
4. Addition of amino group to arsenophenol
→ Diaminodioxyarsenobenzol – Salvarsan, Compound 606
o First antimicrobial drug
o Use of Salvarsan: working against spirochetes – Treponema
pallidum = cause of syphilis
o Activation of Salvarsan in vivo → Oxophenarsine
o Treatment with arsenicals prolonged (18 months) + unpleasant → combination
therapy with mercury and/or bismuth → destruction all spirochetes
§ Prevention appearance of resistance + disease recurrence

PRONTOSIL
Gerhard Domagk (1895-1964)
- German physician
- Failure of medicine to treat battle wounds in World War I → find cure for infectious diseases
- Continued in line of research initiated by Ehrlich at IG Farben laboratories in Wuppertal
1. Synthesis of potential antibacterials by chemists
2. Testing by Domagk on animals + in vitro
o Particularly: test organism against highly virulent Streptococcus hemolyticus
o Involvement of assistants + animal-care support staff
o 1929: Around 30 new products tested per week
3. Abandonding work with quinine derivatives and compounds containing gold →
working with azo dyes
§ Binding to various cells
§ Used as bacterial stains
4. 1932: Addition sulfur atoms to the dye
5. Success after one improvement
→ Sulfamidechrysoidine – Prontosil
§ No activity against streptococci in vitro
§ Activity/protection of infected mice
= active in vivo, not active in vitro
§ 1936: Tested on humans
• Side-effect: red skin (due to the dye)
• Recovery from infection
- 1939: Nobel Prize
- Discovery of Sulfanilamide
o In vivo metabolization of Prontosil → breakdown into active form: Sulfanilamide
o Function in bacteria: competitive inhibitor of
hydropteroate synthetase (DHPS)
§ DHPS: enzyme involved in folate biosynthesis
• Folate: produced by bacteria → needed
for growth
• Blocking folate = blocking growth of
bacteria
o Used in combination with trimethoprim
§ Trimethoprim: folate biosynthesis blocker
• Different part of pathway of folate production blocked compared to
sulfanilamide

, → Co-trimoxazol
PENICILLIN
Alexander Fleming (1881-1955)
- Studied use of Salvarsan
- Studied antimicrobial activity in nasal mucus and tear fluid
→ discovery of lysozyme
o Too big molecule to use
- 1928: Contamination on Staphylococci plates → Penicillium notatum fungus killed
staphylococci
→ Penicilin
o Activity secreted by fungus
o Low toxicity
o Drawbacks
1. Unable to isolate compound in high quantities
2. Not tested on infected animals
3. Unable to determine structure
→ not of interest to chemist

Florey and Chain
- Chemists working on antibacterial compounds
- Studied Fleming’s work on lysozyme
- Studied Fleming’s other discovery → interest in Penicillin
a) Different fungus: Penicillium chrysogenum
b) Different culturing techniques
→ successful isolation larger quantities penicillin → testing possible on
patients
- 1945: Nobel Prize
- Penicillin
o Treatment
§ Wounds on battlefield
§ Surgical wounds
§ Use for STDs → soldiers with gonorrhoea
• Treatment of STD = faster recovery than wounds = first use of
Penicillin during war – soldier back to fight quicker
o One class of β-lactam antibiotics
Penicillins Cephalosporins Carbapenems

STREPTOMYCIN
Selman Waksman (1882-1973)
- Soil microbiologist
- 1940: Systematical screening soil microorganism for production antimicrobial compounds
o Natural compounds produced by one microorganism against other microorganisms
- Discovery 10 different antibiotics
o Term ‘antibiotic’: opposite of symbiose between microorganisms = antibiosis –
compounds needed to fight other microorganisms, involved in antibiosis = antibiotics
→ Streptomycin

, o Produced by Streptomyces griseus
o First antibiotic effective against Mycobacterium
tuberculosis
§ Disease: tuberculosis
o Treatment of tuberculosis
§ Effective: 2-3 weeks → recovery
§ High relapse rate: >80%
§ Relapsed patients more difficult to treat
§ Prolonged combination therapy successful
• Cause: biphasic killing
= First days of treatment sensitive
population (95-99%) killed, persistent
population stays, different state =
more difficult to kill, more time
necessary
• Treatment
1. Two months intensive course
o Isoniazid
o Ethambutol
o Pyrazinamide
o Rifampicin
2. Four months continuation course
o Isoniazid
o Rifampicin
- 1952: Nobel Prize
- Waksman screening platform → golden age of antibiotics

o After Wakmans screening discovery → discovery lots of antibiotics in short period of
time
o Antibiotic Innovation Gap
§ (Almost) no new discoveries
§ Reasons
1) Scientifically: ‘easy’ targets were found, drug screening for new
antibiotics leading to re-discovery same lead compounds → discovery +
development antibiotics scientifically more complex, expensive and time
consuming
2) Economically: antibiotics provide poor return on investment relative to
other classes of drugs + new promising drugs only used in problematic

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