Discovery of Antibiotics Flashcards
Give the 7 types of natural products?
Antibacterial Anti fungal Anticancer Antimalaria Anti parasitic Immunosuppressant Herbicide
Give an example of a of an antibacterial, an anti fungal,
an anticancer, an antimalaira and an anti parasitic?
Penicillin G Aphotericin Doxorubicin Artemisisin Avermectin
Give an example of a herbicide?
Bialaphos
Give an example of an immunosuppressant?
Rapamycin
Define natural products?
A small molecule produced by a living organism, a secondary or specialised metabolite produced by a microorganism (fungi, bacteria, arches) or plant.
Who developed the magic bullet?
When and what was it?
Paul Ehrlic (1854-1914) Salvarsan, a selective toxicity treatment for syphilis.
Who discovered penicillin?
Fleming, 1928. Originally termed ‘mould juice’.
What did Waksman discover?
Streptomycin, 1943.
First effective treatment for TB.
Saved Bob Dole, a 1926 republican president nominee.
Describe filamentous acitnomycetes?
Soil bacteria, produce geosmin (soil smell), produce a number of natural products: Streptomyces make approx. 60% of all clinically important antibiotics in use today
(Actinorhodin, Coelimycin).
Sporalting bacteria.
Give the life cycle of sporulating bacteria and state at which point natural products are produced?
- Spore dispersal
- Spore germination
- Outgrowth of substrate feeding mycelium
- Formation of reproductive aerial hyphae
- Chromosome segregation and separation
- Spore formation.
Formation of reproductive aerial hyphae: antibiotics are produced to protect nutrients released from dead substrate mycelium (normally at this point where the natural products are produced to outcompete there neighbours).
Describe the Waksman Platform?
A method of natural product discovery.
- Isolate actinomycete bacteria
- Antibacterial bioassay screen (assay ability to inhibit growth)
- Small scale fermentation
- Bioactivity-guided fractionation (and purification)
- Chemical characterisation.
When was the golden era of antibiotic discovery?
1908-1962
Why has there been decline in antibiotic discovery?
- Low profitability (acute vs. chronic conditions)
- Short window of use (e.g. development of resistance)
- R&D is time consuming & expensive and there are issues with rediscovery
- Regulatory issues
What happened from 1962-2011?
Golden age of medicinal chemistry and innovation gap.
What are we now entering?
The natural product renaissance: the new era of natural product discovery ad engineering.
What was the longitude prize 2014?
£10 million for creating a cost-effective, accurate, rapid and easy-to- use test for bacterial infections that will allow health professionals worldwide to administer the right antibiotics at the right time.
What does the natural product renaissance include?
Bioprospecting, genome mining, exploiting biosynthetic dark matter, natural products from the uncultured (Ichip and eDNA), combinational biosynthesis.
What are the most common classes of natural products?
Polyketides, non-ribosomal peptides and lantipeptides.
What is bioprospecting?
Looking for new natural products in under explored environmental niches.
Complete: novel bugs=
novel drugs
Give a few examples of novel niches?
Deserts, ants, deep sea
What happens as the phylogenetic relatedness decreases?
Their chemistry diversity increases.
Describe the findings when looking at arid soils?
100 soil samples were looked at using a 454 amplicon sequencing A- and KS-domians in order to estimate biosynthetic diversity.
- soils from the same geographic are were more similar
- soils from the same soil type were more similar
- arid (desert) soils were the most biochemically diverse.
What are endophytes?
Bacteri (or fungi) that live inside pants and do not cause disease. They prime the plant immune system and often produce bioactive compounds that help prevent the plant from becoming infected (antibiosis).
Describe the marine environment as a novel niche?
Hugely under-explored. Several new drugs in development from newly discovered actinomytes and mycobacteria, the majority of new compounds were isolated from bacteria living in symbiosis with marine animals.
Give some examples of new compounds from the marine environment?
Abyssomicins: polycyclic antibiotics from a new marine acitonomyete genus named Verrucosispora
- inhibits folic acid biosynthesis, old target but new drug
Salinispora sp. (salinosphoramide- anti cancer drug).
Give the names of the types of bugs which provide novel niches?
Beewolf digger wasps,
Allomerus trap ants,
Tetraponera Penzigi ants,
Acromyrmex leafcutting ants
Discuss Beewolf digger wasps?
Beewovles prey on honeybees to provide food for their larvae housed in an underground chamber. They protect their larvae by covering the brood cell with endosymbiotic actinomycetes harboured in their antennae (the white stuff!).
Discuss allomerus trap ants?
Live on plants, never leave. Winged insects get trapped and get eaten. They strip of the leaves from the plants and cultivate a fungus (in relatively pure form) which they then use to build honeycomb structures.
Discuss tetraponera penzigi ants?
Plant ants that live on acacia trees in Africa. They live inside hollow thorned structure called domatia. They cultivate a fungus (in relatively pure form) for food and associate with antibiotic-producing. Found streptomyces formica, which led to the discovery that activity of chloramycin increases with the number of chlorine molecules it has.
Discuss acromyrmex leaf cutting ants?
They cut the leaves take them to the nest and de wax them and feed them to a fungus that produce what they feed off. The fungi and the ants rely on each other.
Antibiotic-producing actinomycetes protect the host and their food supply.
Newly emerged ants are inoculated and bloom with pseudonocardia within hours. Older ants lose the most of the white covering (to the breast bone) and acquire a more diverse micro biome. Only the older workers leave the next, because they are less prone to infection. Microbes prevent the food supply and ants from disease.
How can actinomycetes staring be identified?
Identifying actinomycete strains: 1. Culture dependent isolation 2. 16S PCR and sequencing 3. Antifungal bioassays Genomics and chemistry together. Bioactivity-guided fractionation (2 molecules found, both known at the time but the genome sequence was used to find the pathway).
