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3s1: Evolution of health and disease > Week 7 > Flashcards

Week 7 Flashcards

1
Q

What is an antibiotic?

A

An antibiotic is any compound that inhibits the growth, or actively kills, microorganisms

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2
Q

What is wrong with the definition of antibiotics?

A

Imprecise
Therefore usually refers to compounds that selectively target bacteria
Modern medicine would be impossible without antibiotics
Often consider compounds used clinically, but antibiotics are found widely in nature

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3
Q

What is an overview of the antibiotic discovery?

A

Salvarsan - 1910 - Paul Ehrlich
Prontosil - 1932 - Gerhard Domagk (both artificial)
Tyrocidine A - 1939 - Rene Dubos
Penicillin G - 1928/1940 - Alexander Fleming
Selman Waksman - 1943 - Streptomycin

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4
Q

What is an overview of streptomyces?

A

Streptomycin - the first treatment for TB
Selman Waksman - Nobel Prize 1952
Starting with Sir David Hopwood, there has been a strong base for Streptomyces genetics research in Norwich for over 50 years
At least 6 research groups currently involved in Streptomyces research in Norwich

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5
Q

What are classes of clincically used antibiotics?

A

Actinomycetes eg Tetracyclines
Other bacteria - Monobactams
Fungal - Penicillins
Synthetic - Azoles

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6
Q

What is an overview of actinomycetes?

A

Actinomycetes are Gram-positive, non-motile bacteria often found in the soil
Also produce a variety of other clinically or agriculturally important compounds, such as anticancer agents, immunosuppressants, anti-fungals, herbicides and insecticides
Streptomyces bacteria belong to a taxonomic group called the Actinomycetes (or “Actinomycetia”)

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7
Q

What is a brief overview of antibiotic discovery?

A

1 - Environmental sample
2 - Plate to identify bacteria and fungi
3 - Individial organism screened for antibiotic production
4 - Fermentation and subsequent purification to isolate pure antibiotic
5 - Clinical testing, scale up and regulatory assessments
6 - New antibiotic

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8
Q

What are specialised metabolites?

A

Specialised metabolites are small molecules that are produced naturally (“natural products”)

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9
Q

What is an overview of the function of specialised metabolites?

A

Molecules have specific roles for producing organisms Usually non-essential but confer an evolutionary advantage to producer - these are evolved traits
Sometimes overlap between functions: some antibiotics may function as signalling molecules, or have inhibitory activities towards other organisms
Some molecules will be multi-functional

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10
Q

What is the microbiome?

A

The microbiome is the sum of the microbes and their
genomic elements in a particular environment

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11
Q

What are contact dependant weapons for microbe competition?

A

T4SS
T5SS
Nanotubes
Outer membrane exchange

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12
Q

What are contact independant weapons for microbe competition?

A

Proteins
Membrane visicles
Tailocins
Phages

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13
Q

What is the famous example of antibiotics use in insect?

A

Leafcutter ants represent a well-studied ancient example that have existed for >50 million years

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14
Q

Why do leafcutter ants needs antibiotics?

A

Form symbiotic relationship with Leucoagaricus gongylophorus but parasitic escovopsis weberi fungi invades and kill mutalistic fungi

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15
Q

Where do leafcutter ants get their symbiotic bacteria?

A

Vertical transmission: queen or nursery workers inoculate new ants with Pseudonocardia, an actinomycete bacterium

Horizontal transmission: ‘SCREEN’ Streptomyces and other actinomycetes from the soil to combat drug resistance

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16
Q

Wha is the predictions when scanning the microbiome on leafcutter ants?

A

The host provides a high level of resources (rewards) to the bacteria to fuel competition
The host uses a vertically transmitted Pseudonocardia strain to create a demanding environment by producing antibacterials
Only bacteria that produce antibacterials (to fight the Pseudonocardia) and are resistant to Pseudonocardia-produced antibacterials (A+R+) can invade
This results in a microbiome dominated by Pseudonocardia and other antibiotic-producing actinomycetes, like Streptomyces

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17
Q

How did they test ants on the ability to feed bacteria?

A

Use of RNA-stable isotope probing (RNA-SIP) test whether Acromyrmex ants supply resources for bacterial growth
Isotopically-labelled (“heavy”) glucose is fed to the ants
RNA is isolated and fractionated based on incorporation of heavy isotopes
RNA sequencing demonstrates that heavy isotopes flow from the host to the RNA of microbial partners

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18
Q

What were the main bacteria that had the c13 glucose?

A

Pseudoncardia (biggest group) and Streptomyces

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19
Q

What are the results when escovopsis is exopsed to fungi food but also pseudonocardia and streptomyces?

A

Control - Escovopsis rapid dominate growth
Pseudocardia - relegate to small patch in corner
Streptomyces - some growth but not near mutalistic fungi

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20
Q

What chemical does pseudoncardia use to kill bacteria?

A

Nystatin - used in medicine

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21
Q

What are the antibiotics produced by streptomyces albus?

A

Antimycin and Candicidin and unknown 3rd
When both knocked out, escovopsis grew but still zone of inhibition

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22
Q

What happens when you cocultivate Leucoagaricus and Escovopsis?

A

Escovopsis goes into overdrive seen with growth on agar plate and chromatogram with metabolite production
An overproduced molecule is Melinacidin IV which is an antibiotic towards psuedocardia
Also produced is Shearinines D and A

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23
Q

What is an overview of shearinines?

A

Shearinines are specialised metabolites produced by the Escovopsis fungus that infects the colony
These molecules are neurotoxins that impact ant behaviour and fitness - struggle to move and disorientated

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24
Q

What is an overview of biosynthetic gene clusters in symbiosis?

A

Dedicated biosynthetic pathways exist in bacteria and fungi for the production of antibiotics (as well as compounds with other activities)
Huge variety of pathway types - often very complex
Genes for these pathways are almost always clustered in bacteria and fungi

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25
Q

What is an overview of the teicoplanin gene cluster?

A

Gene cluster encodes proteins for the teicoplanin regulation, biosynthesis, self-resistance and export

26
Q

What is an overview of understanding bioactive moleculesin bacteria?

A

> 700,000 bacterial genome sequences
Less than 3% of gene clusters characterised
Huge potential for bioactive molecules but not realised

27
Q

What is an overview of the bioactivity of streptomyces formicae?

A

46 bioactive molecules
Pathway 26 antibiotic for Bacillus subtillis and MRSA
Pathway 30 antifungal for Candida Albicans and Lomentospora prolificans

28
Q

What is an overview of Formicamycins?

A

Streptomyces formicae - pathway 26
Powerful new antibiotic - MRSA does not evolve resistance to formicamycins in vitro

29
Q

How did they test for the benefit of Pseudomonas for plants?

A

100s of Pseudomonas strains isolated from potato fields and screened for suppression potato pathgens eg phytophthora infestans
A subset of 70 strains were subjected to whole genome sequencing

30
Q

How did they use phylogeny in Pseudomonas supressing pathogens?

A

Phylogeny with coded message for whether it is supressive and how supressive it is
Repeat with genes

31
Q

What chemicals can Pseudomonas bacteria make in response to plant pathogens?

A

Cyclic lipopeptides like Tensin
Hydrogen cyanide

32
Q

Do cyclic lipopeptides and HCN contribute to on-plate inhibition?

A

Pseudomonas sp. Ps619 produces tensin (a cyclic lipopeptide) and HCN
Grow on plate with Streptomyces scabes
Some plates has Tensin and/or HCN inhibition

33
Q

What were the results for cyclic lipopeptides and HCN contribute to on-plate inhibition?

A

Wildtype pseudo - Inhibits S.Scabies significant zone of inhabtition
Tensin inhibited mutant - Increased growth of S.Scabies
HCN mutant - Large growth of S.Scabies
Tensin and HCN mutant - Pseudomonas overgrown by S.Scabies

34
Q

What happens when potatoes are grown with S.Scabies and with modified Pseudomonas?

A

Control no S.Scabies - no disease
With S.Scabies - Disease present
S.Scabies and Pseudo - Reduced disease
S.Scabies and Pseudo without tensin - large amount of disease
S.Scabies and Pseudo without HCN - reduced disease
S.Scabies and Pseudo without HCN and tensin - Large amount of disease present

35
Q

What are areas an antibiotic can target and example of antibiotic?

A

Cell Wall synthesis - Pencillins
30S subunit - Tetracyclines
RNA synthesis - Rifampicin

36
Q

How widespread is antibiotic resistance?

A

Infectious diseases make up 7 out of 10 leading causes of death in LIC
Predicted 10 million people will die a year from antimicrobial resistant infection in 2050 up from 700,000

37
Q

How widespread is carbapenem-resistant Acinetobacter baumannii?

A

Most of Asia + North Africa + South America - 80+% stains resistant
HIC lower than LIC - Japan, Australia and Canada - 10-20%
Low in North an West europe - <5%

38
Q

What are examples of mechanisms of antibiotic resistance?

A

Efflux pumps
New protein with same metabolic capacity
Target site modification
Inactivation of antibiotic

39
Q

What is a key example of antibiotic resistance mechanism?

A

β-lactamases that degrade beta-lactams
An enzyme that hydrolytically breaks the β-lactam ring in penicillin and other β-lactams
First discovered in 1940

40
Q

How has nature and medicine countered B-lactamases?

A

Clavulanic acid inhibits beta-lactamases
Used in combinations to restore activity of beta-lactams, such as amoxicillin
Clavulanic acid is naturally produced by Streptomyces clavuligerus, which also produces multiple β-lactam antibiotics
”Combination therapy” in nature and medicine

41
Q

How does antimicrobial resistance develop?

A

Random mutagenesis: mutants that confer increased survival towards an antibiotic are selected for during antibacterial treatment

42
Q

How did they experimentally show antimicrobial resistance?

A

Experiment used trimethoprim (TMP), which inhibits folate biosynthesis
Distinct mutational events in genes that were mutated at least twice independently
Expected mutations in folate metabolism genes
Also stress response genes that are important in general resistance to antibiotics and toxins
Mutations to genes involved in transcription/translation, which have been shown to affect TMP resistance, as well as new genes not previously associated with resistance

43
Q

How can low drug concerntration facilitate adaptation to antibiotics?

A

Low levels can provide a platform to adapt to higher levels of antibiotics
0 to 3000 : 0 to 30 to 3000 time to adapt: >250 hours compared to 127 hours

44
Q

How can antimicrobial resistance spread?

A

Horizontal gene transfer: entire genes (or clusters of genes) are transferred from one bacterium to another as mobile genetic elements.
More dangerous due to the capacity for spreading complex multi-gene resistance mechanisms

45
Q

What is an overview of horizontal transmission?

A

4 main methods:
Transformation
Conjugation
Transduction
Outer membrane vesicles

46
Q

Why is horizontal transmission a massive problem?

A

Plasmid conjugation is the major transmitter of AMR
Can happen between different species
Can transfer complex resistance mechanisms
Can carry multiple resistance mechanisms

47
Q

What is an example of an antimicrobial resistant plasmid?

A

pKP048
Klensiella pneumoniae
Resistant to Carbapenems, Aminoglycosides, Cephalosporins, Macrolides, Fluoroquinolones

48
Q

What is an overview of Glycopeptides antibiotics?

A

Natural products produced by actinomycete bacteria
Used to treat multi-drug resistant Gram-positive bacterial infections such as methicillinresistant Staphylococcus aureus (MRSA)
Until recently, two compounds used clinically: vancomycin and teicoplanin
Global market of around $3 billion

49
Q

What are examples of Glycopeptide antibiotics?

A

Vancomycin - Produced by Amycolatopsis orientalis Discovered in 1952 from a Borneo soil isolate
Teicoplanin - Produced by Actinoplanes teichomyceticus
Discovered in 1977 from an Indian soil sample

50
Q

What is an overview of glycopeptide biosynthetic gene clusters?

A

Teicoplanin gene cluster
Gene cluster encodes proteins for the teicoplanin regulation, biosynthesis, selfresistance and export
Clusters and resulting molecules are the result of extensive evolutionary processes

51
Q

What is an overview of the evolution of glycoprotein production?

A

> 1,000 Mya - Ancestral enzymatic and regulatory machinery (Gtf ancestor)
1,000-400 Mya - Evolution of assembly lines for core peptide biosynthesis (
400-<150 Mya - Further acquisition/evolution of enzymatic machinery (e.g. glycosyltransferases, “Gtf”) to further diversify molecules

52
Q

What is an overview of peptidoglycan?

A

Glycopeptide target
The peptidoglycan forms an integral part of the bacterial cell wall
A polymeric material formed from sugars (glycans) and amino acids

53
Q

What is an overview of glycopeptide mechanism of action?

A

Forms 5 hydrogen bonds with the D-Ala-D-Ala termini of the bacterial peptidoglycan
Very specific and very strong three-dimensional interaction that inhibits both transglycosylation and transpeptidation
Osmotic pressure kills the cell in the absence of a well structured peptidoglycan

54
Q

What is an overview of the belief on glycopeptide resistance?

A

It was speculated that the mechanism of action of the antibiotic and the complexity of developing resistance meant that resistance was highly unlikely in clinical bacterial strains

55
Q

What is seen with resitance to glycopeptide resistance?

A

Within 10 years Vancomycin-resistant enterococci (VRE) represented >25% of enterococci associated with bloodstream infections in hospitalized patients in the United States

56
Q

How do bacteria become resistant to glycopeptide?

A

Replacement of one hydrogen bond with an oxygen-oxygen lone pair repulsive interaction
This causes a >1000 fold decrease in afinity
Resistance therefore caused by the replacement of one atom in a molecule

57
Q

How did glycopeptide resistance arise?

A

Producing organisms need to be resistant to the antibiotics they produce
Horizontal gene transfer of resistance genes into clinical pathogens

58
Q

When did glycopeptide resistance arise?

A

Streptomyces (natural resistance: millions of years)
Vancomycin-resistant Enterococcus (resistance acquired in the 1980s)
Vancomycin-resistant Staphylococcus aureus (resistance acquired in the 2000s)

59
Q

What is an overview of the soil resistome?

A

Isolated 480 Streptomyces strains and screened them against 21 antibiotics
The strains were each resistant to an average of seven antibiotics
Huge amounts of antibiotics have been dispersed into the environment
Antibiotics traditionally used in agriculture
Transfer of resistance mechanisms from the soil to pathogens can occur

60
Q

How can you overcome glycopeptide antibiotic resistance?

A

Amidino vancomycin aglycone
Swapping a O= with a NH therefore no repulsion
Redesigned antibiotic retains activity against vancomycin-resistant E. faecalis
Required the full synthesis of the molecule: possibly too expensive for clinical use

61
Q
A

3s1: Evolution of health and disease (10 decks)

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