PHAR1101 Study Guide - Quiz Guide: Arsphenamine, Viral Disease, Prontosil

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18 Jun 2018

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Penicillin/Antibiotics

Antibiotic era:

oSalvarsan: 1911 - Ehrlich

Proved that fatal infectious diseases were manageable with drugs

Fostered hospital microbiology infrastructure

Well equipped labs

Handling lots of patient samples

Sample analysis protocols

Dosing guidelines

Trained medical, nursing + scientific staff

oProntosil: 1935- Domagk

Limitations of salvarsan and Sulfa drugs

Narrow spectrum of action - did not kill a large range of bacterial species

Toxicity to patient with salvarsan- arsenic

Skin stained with Prontosil - not other sulphonamides

Bacterial resistance

Penicillum mould

1870: Burdon-Sanderson UK attracted by Pasteur's germ theory

1871: reports of penicillum mould (from fruit and jam) to stop bacterial growth

Joseph Lister found antiseptic properties on phenol

Observed curative properties of penicllium soaked dressings on infected wombs

Alexander Fleming

Born 1881 Scotland

Watched soldiers die of infected wounds in medical crops WW1

Noted failure of antiseptics to cure internal infections

1928: director, inoculation lab, st Mary's hospital, London

oWorked on antibacterial properties of human nasal secretions (lysozyme)

A fluke observation from Fleming

1928: he took a 2 week vacation

Left agar plates on lab bench

Unusual cold snap

Returned to work and noticed inhibitory effect of mould of bacterial growth

Half-hearted follow up

Made bright yellow filtered broth from Penicllium notatum mould

oVery active against growing Staph cultures as well as against other bacterial

species

Non-irritating if applied directly to the tissue: safe in injected into HEALTHY mice

Couldn’t purify active chemical (unstable)- "forgot" drug for 12 years

Howard Florey

Adelaide pathologist

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Professor - Oxford

1937: hired Ernst Chain - biochemist

Chain overcame penicillin instability and extraction problems

oPrepared as a stable lyophilised salt as ph. 5-8

March 1940: staph infected mice full recovery

Human testing

FEB 1941

43 y.o. policeman with invasive Strep/Staph infections

o200 mg penicillin (i.v. drip) + 100mg every 3 hours

24 hours - strong recovery but drug ran out after 3 days

Administered recycled penicillin - urine

Subsequent patient also died before success with 2 patients

Sam

1940/1: two papers published in the Lancet

British drug companies unable to help - war pressure

US $5000 grant from Rockefeller Foundation allowed travel to US

Links with US Dept. Agriculture researchers (isolated high yield Penicillium strain)

Consortium with US companies

oPerfected large scale deep vat growth of pencillium mould

1942 USA

500 deaths in club fire - Boston

220 survivors - treated with Penicillin

Military amazed with effectiveness

1944: monthly US production > 130 billon units

Sufficient for Allied troops at Normandy invasion 1944

Making penicillin

1943: both US/UK teams made drug crystals but found they were working with

different penicillins

Many variants soon isolated from Penicillin broths

WW2>1000 scientists, 39 unis and companies tried to make drug synthetically

1946: Hodgkin UK solved unusual b-lactam structure

Semi-synthetic penicillins

Wide range of penicillin family members- chemists

Ampicillin, amoxicillin

Sheehan

American organic chemist

9 year project at MIT

1957: first total synthesis of penicillin

Forming b-lactam ring was obstacle

Made 6-aminopenillianic acids

Key building block for synthetic penicillins

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Strominger

Professor of Pharmacology US

Studied bacterial well wall and 30 enzymes needed to make it

Peptidoglycan- chains of amino sugars crosslinked by small peptides

1965: ground breaking paper of effect of penicillin on cell wall synthesis

Identified transpeptidase as main target for penicillins

Bacterial cell wall

Rigid structure which helps bacteria maintain their shape

oDifferent from the cell wall of plant cells or the plasma membrane of

eukaryotic cells

Cell wall is dynamic - remodelled during cell growth, motion

Golden age

After WW2 - secrecy concerning penicillin ended

Allowed commercial development of many new drug classes

Widespread, global screening of microbes for new drugs - derived from soil samples

Many lethal diseases receded (syphilis, pneumonia)

Drug resistance

Loss of effectiveness is common for all antibiotics

Bacteria can develop resistance spontaneously

Acquire plasmids

Consequences of drug resistance

More antibiotics are ineffective

Resorting to nastier drugs

Multidrug resistant strains - hospital's

Much smarter with existing drugs

Economic problem

Drug companies need to receive adequate returns on their antibiotic investments

We need cheaper ways of discovering and testing antibiotics in humans

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Document Summary

Antibiotic era: salvarsan: 1911 - ehrlich. Proved that fatal infectious diseases were manageable with drugs. Trained medical, nursing + scientific staff: prontosil: 1935- domagk. Narrow spectrum of action - did not kill a large range of bacterial species. Skin stained with prontosil - not other sulphonamides. 1870: burdon-sanderson uk attracted by pasteur"s germ theory. 1871: reports of penicillum mould (from fruit and jam) to stop bacterial growth. Joseph lister found antiseptic properties on phenol. Observed curative properties of penicllium soaked dressings on infected wombs. Watched soldiers die of infected wounds in medical crops ww1. Noted failure of antiseptics to cure internal infections. 1928: director, inoculation lab, st mary"s hospital, london: worked on antibacterial properties of human nasal secretions (lysozyme) 1928: he took a 2 week vacation. Returned to work and noticed inhibitory effect of mould of bacterial growth. Made bright yellow filtered broth from penicllium notatum mould: very active against growing staph cultures as well as against other bacterial species.

PHAR1101 Study Guide - Quiz Guide: Arsphenamine, Viral Disease, Prontosil

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