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3s2: Infection and Immunity > Week 11 > Flashcards

Week 11 Flashcards

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1
Q

How important are antibiotics for human health?

A

Modern medicine would be impossible without
antibiotics
Kill infectious microbes, without harming you
Increased average life expectancy by 23 years

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2
Q

What are the groups of antibiotic source and antibiotic from them?

A

Actinomycetes (most common) - Tetracyclines
Other bacteria - Monobactams
Fungal - Penicillins
Synthetic - Azoles

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3
Q

What was an overview of antibiotic in TB treatment?

A

1943- Selman Waksman discovers streptomycin - the first treatment for TB

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4
Q

Why do bacteria make antibiotics?

A

Are they signalling molecules or chemical weapons? (Both probably)
Each species makes ~3 antibiotics in vitro and the rest are “silent” - we don’t know how to switch them on

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5
Q

What is an overview of streptomyces antibiotic production?

A

Streptomyces bacteria encode ~25 secondary metabolites per species
>600 Streptomyces species are known

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6
Q

How do antibiotics work?

A

Clinically useful antibiotics work by inhibiting essential machinery that is unique to bacterial cells

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7
Q

What are examples of antibiotics and their target?

A

Cell membrane - daptomycin
DNA gyrase - Quinolones
RNA polymerase - Rifampcin
Cell wall synthesis - Beta lactams
Folic acid biosynthesis - Sulfonamides

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8
Q

What is the traditional antibiotic discovery pipeline?

A

Isolate from environment (typically soil)
Bioassay for antibiotic productin
Purify antibiotic
Identify structure of antibitoic

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9
Q

Where did it all go wrong for antibiotic discovery?

A

Discovery is hard and hampered by problems of rediscovery in soil
Resistance is inevitable - accelerated by misuse
Antibiotics are cheap and not profitable
Nobody wants to pay for antibiotic discovery

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10
Q

What was the ‘Golden Age’ of antibiotic discovery?

A

1940 to 1960

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11
Q

What is an overview of the future of antibiotics?

A

In the 1940-50s scientists focussed on soils but new environmental niches give new strains and new scaffolds
>97% of antibiotics are silent, i.e. not made under lab conditions. Switching them on will give us new antibiotics

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12
Q

What is an overview of Leafcutter ants, symbionts and threats?

A

Leafcutter ants - Acromymrex
Food fungus - Leucoagaricus
Bacteria - Pseudonocardia and Streptomyces
Parasitic fungus - Escovopsis

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13
Q

Where do leafcutter ants get their bacteria?

A

Vertical transmission: queen or nursery workers inoculate new ants with Pseudonocardia
Horizontal transmission: They ‘SCREEN’ Streptomyces from the soil to combat drug resistance

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14
Q

What is an overview of RNA stable isotope probing for identifying symbionts?

A

Feed ants 12C glucose or 13C glucose for 14 days
Isolate RNA, separate heavy and light fractions on CsTFA. Amplify and sequence 16S rRNA

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15
Q

What were the results of RNA stable isotope probing for identifying symbionts?

A

Primarily Pseudonocardia and Streptomyces, as expected, though all bacterial groups such as wolbachia were also present showing sugar secretions were enjoyed by all

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16
Q

How does Pseudonocardia promote symbionts?

A

Pseudonocardia creates a demanding environment through antibiotic enviroment
Streptomyces often is resistant so can live their and produces its own antibiotics

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17
Q

What are antibiotics that pseudonocardia to kill escobopsis?

A

Antimycin
Nystatin P1
Candicidin

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18
Q

What antibiotics are produced by Escovopsis to counter ants and bacteria?

A

Melinacidin IV - antibiotic
Shearinine D and A - insect neurotoxin
Emodin - Feeding deterent

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19
Q

Can we find new antibiotics from fungus growing ants?

A

Streptomyces formicae a bacteria found on ants has 45 gene pathways
Pathway 28 - antifungal effective against Candida Albicans and Lomentospora prolificans (doesnt have known cure)
Pathway 33 - antibiotic effecitve against Bacillus subtilis and MRSA

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20
Q

What is an overview of Formicamycins?

A

MRSA does not evolve resistance to formicamycins in vitro
Target both DNA gyrase and Fatty acid biosynthesis
Often resistant in 10 generation

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21
Q

What happens when you inhibit gene pathway 33?

A

No formicamycins but something more potent is produced
So using comparison of RNA transcripts can narrow down which gene is responsible
This is believed to be pathway #8

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22
Q

What is an overview of Streptomyces formicae pathway 8?

A

Nonribosomal peptide
That inhibits MRSA

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23
Q

What is an overview of the discovery of Salvasan?

A

The 606th tested compound proved effective in laboratory animals
Arsphenamine, named Salvarsan
Potentially lethal for patients but did cure infections previously considered hopeless
Proved some chemicals could selectively kill microbes

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24
Q

What is an overview of Paul Elrich thought that led to salvarsan discovery?

A

Indicated fundamental difference between cell types
Searched for “magic bullet” that would kill microbial pathogens without harming human host
Synthesized arsenic compounds to treat syphilis, caused by spirochete Treponema pallidum

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25
What is an overview of Alexander Fleming?
Named compound penicillin Showed effective in killing many bacterial species Unable to purify, he later abandoned research
26
What is an overview of Ernst Chaina and Howard Florey work?
~10 years later, Ernst Chain and Howard Florey purified, tested compounds in 1941 on police officer with life-threatening Staphylococcus aureus infection
27
What was the impact of Ernst Chaina and Howard Florey work?
Patient improved dramatically within 24 hours Supply of purified penicillin ran out and he later died WWII spurred research and development; penicillin G was first antibiotic (naturally produced antimicrobial)
28
What is an overview of streptomycin antibiotic history?
Selman Waksman purified streptomycin from soil bacterium Streptomyces griseus Pharmaceutical companies examine soil samples from around world for microbe produced antibiotics
29
What is the history of penicillin modification?
Discovered in 1960s that altering structure of penicillin yields new medications
30
What are antibiotics?
Small molecules produced by microorganisms that kill or arrest growth of, other microorganisms (anti-bacterial, anti-fungal) Since extended to include synthetic compounds
31
What is an overview of natural produced antibiotics function?
Naturally produced antibiotics are secondary metabolites (not required for growth) and can also have a broader spectrum of activity e.g. anti-cancer
32
What are the major natural sources of antibiotics?
Actinomycetes - 7900 (66%) Other bacteria - 1400 (12%) Fungi - 2600 (22%)
33
What is an overview of actinomyces use?
Out of 100 used in clinical therapies around 50 are actinomycete derived
34
What are the characteristics of Antimicrobial Medications?
Selective Toxicity: cause greater harm to microbes (Interfere with essential structures or properties common in microbes but not human cells) Antimicrobial Action Bacteriostatic chemicals inhibit bacterial growth (Immune defenses must still eliminate) Bactericidal chemicals kill bacteria
35
What is an overview of spectrum of activity?
Broad-spectrum antimicrobials affect a wide range of microbes Narrow-spectrum antimicrobials affect limited range
36
What is an overview of broad spectrum antimicrobials?
Important for treating acute life-threatening diseases - especially when no time to culture for identification Disrupt normal microbiota that help in keeping out pathogens
37
What is an overview of narrow spectrum antimicrobials?
Requires identification of pathogen, testing for sensitivity Less disruptive to normal microbiota
38
What is an overview of minimum inhibitory concerntration?
Minimum inhibitory concentration (MIC) - lowest concentration of the drug that inhibits visible bacterial growth.
39
What is an overview of minimum bactericidal concentrations?
Minimum bactericidal concentration (MBC) – lowest concentration that kills 99.9% of the starting number of bacterial cells.
40
What is an overview of testing activity of antimicrobial compounds?
Kirby-Bauer Disk-diffusion test Broth dilution test Microbroth dilution test E-test
41
What is an overview of Kirby-Bauer disk diffusion test?
Kirby-Bauer Disk-diffusion test – standardized antibiotic testing assay Measure with ruler the zone inhibition around antimicrobial disks
42
What is an overview of Broth dilution test?
Broth dilution is a technique in which containers holding identical volumes of broth with antimicrobial solution in incrementally (usually geometrically) increasing concentrations are inoculated with a known number of bacteria When noticable lack of cloudy or other visible trait
43
What is an overview of microbroth dillution test?
Multiple microtiter plates are filled with a certain broth, according to the needs of target bacteria. Varying concentrations of the antibiotics and the bacteria to be tested are then added to the plate. If the broth became cloudy or a layer of cells formed at the bottom, then bacterial growth has occurred. The results of the broth microdilution method are reported in Minimum Inhibitory Concentration (MIC)
44
What is an overview of E-test?
E-TEST is a well-established method for Minimum Inhibitory Concentration (MIC) determinations in microbiology laboratories around the world. ETEST consists of a predefined gradient of antibiotic concentrations immobilized on a plastic strip
45
What is an overview of Beta lactams?
Penicillins, Cephalosporins and other β-Lactam Antibiotics all have β-Lactam ring Bacterial cell walls are unique, contain peptidoglycan; a great target for medications Competitively inhibit enzymes that catalyze formation of peptidebridges between adjacent glycan strands; disrupt cell wall synthesisW
46
What do Beta-Lactams bind to?
Called penicillin-binding proteins (PBPs) since bind penicillin
47
What do Beta-lactams change in effectiveness depending on bacteria?
Peptidoglycan of Gram-positives is exposed Outer membrane of Gram-negatives blocks their access Some bacteria synthesize β-lactamase, which breaks critical β-lactam ring; many different types
48
How can ribosomes be targeted by antibiotics?
Prokarykotes are 70S (made up of 50S and 30S subunits) Eukarykotes are 80S ribosomes 60S and 40S) Tetracyclines block attahcment of tRNA to rRNA Macrolides prevtn continuation of protein synthesis
49
What is an overview antibiotic folate inhibtors?
Folate inhibitors are among most useful Sulfonamides (PABA synthase), trimethoprim (dihydrofolate reductase (DHFR)) inhibition of folic acid and coenzyme required for nucleotide synthesis Animals lack enzymes to synthesize folic acid; required in diet
50
What is an overview of cell membrane targeting antibiotics?
Daptomycin inserts into cytoplasmic membrane, Used against Gram-positives resistant to other antibiotics but Ineffective against Gram-negatives; cannot penetrate outer membrane Polymyxin B binds to membranes of Gram-negatives
51
How long did in take in experiments for E. coli to become resistant to 3000x trimethiprim?
280 hours
52
What is an overview of antibiotic resistance cases and deaths?
USA 2019 2.8 million cases 36,000 deaths
53
What is an overview of antibitiocs year of release and resistant germ identified?
Penicillin - 1941 resistance in Staph Aureus 1942 Methicllin - 1960 resistance in Staph Aureus 1960 Caspofungin - 2001 resistance in Candida Albicans 2004
54
How does antimicrobial resistance spreads?
Bacteria and fungi are everywhere, some help is and some infect and cause disease in people, animals or plants Antibiotics are used to kill microbes that cause infection. But, microbes find a way to resist and survive Antibiotic-resistant bacteria can multiply. Some can transfer their resistance genes to other organisms, passing on resistance Once antibiotic resistance emerges, it can spread into new settings and between countries
55
How does antimicrobial resistance genetics spreads?
Plasmids, transposons and phages via Transduction (transfer to between bacteria by phages) Conjugation (resistance genes transfered through contact) Transfromation (pickup genetic material from dead cells)
56
What is an overview of one health and AMR?
Health of the people is connected to the health of animals and the environment (soil, water) Sewage contains frequent low levels of antibiotics and high level usage in agriculture so allows mutations to occur
57
What are mechanisms for antibiotic resistance?
Efflux pumps to remove Decrease memebrane permability ie remove porins Stop the antibiotic binding its target (evovle target protection or modify target site) Replace tagret ie new ezyme for same pathway Break down the antibiotic with enzyme
58
What is an overview of Clostridiodies difficile cases?
2011 to 2015 320 cases per 100,000 to 160 cases per 100,000
59
How has Gonorrhea antibiotic reistance from 2008 to 2016?
Ceftriaxone (last reccomneded treatment) - 15% to 27% Penicllin - 12% to 20% (no longer reccomended in 80s)
60
What is an overview of CDC serious microbe threats and resistance from 2012 to 2017?
ESBL-Enterobacteria - 132,000 to 197,000 cases Vancomycin-resistant Enterococci - 85,000 cases to 55,000 cases Methicllin-resistant Staphlococcus aureus - 401,000 cases it 323,700 cases
61
What is an overciew of Staphylococcus aureus antibiotic resistance?
Increasingly important cause of healthcare-associated infections since 1970s In 1990s, emerged as cause of infection in the community
62
What can Staphylococcus aureus infections cause?
Bacteremia – a blood infection Deep abscesses –an abscess that occurs below the skin surface Endocarditis – an infection on the valves of the heart
63
What is an overview of vancomycin usage?
Vancomycin remains a 1st-line therapy for severe infections possibly caused by MRSA Final therapy decisions should be based on results of culture and susceptibility testing
64
How do beta lactams inhibits bacteria?
Transpeptidases binds D-Ala D-Ala which release one of them Beta lactams inhibits this
65
What is an overview of PBP2a?
PBP2a (mecA) has low affinity for beta-lactams this allows for the same molecuar product but with a different enzymatic process
66
What is an overview of vancomycin?
Vancomycin acts as a dimer and forms H bonds with the D-Alanyl-D-Alanine termini on the stem of NAM/NAG peptides of cell wall precursors to inhibit transpeptidation and transglycosylation of the cell wall.
67
Why does vancamycin inhibit bacteria?
This binding of vancomycin to the D-Ala-D-Ala prevents the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix.
68
What is an overview of Vancomycin resistant MRSA
VISA - vancomycin intermediate MRSA, have thickened cell walls. VRSA - vancomycin resistant MRSA, have vancomycin resistance genes
69
What is an overview of vancomycin genes?
Vancomycin and related glycopeptide antibiotics are natural products made by Amycalotopsis and Streptomyces bacteria. These bacteria also carry genes which encode resistance to vancomycin - otherwise suicide
70
What are natural population having vancomycin resistance genes?
vanRSHAX vanRS vanHAX
71
What is an overview of vanRSHAX?
The vanRSHAX genes have now spread from the producing bacteria in the soil to enterococci (1980’s) and then MRSA (2000’s) giving us VRSA.
72
What is an overview of vanRS?
The vanRS genes encode a signal transduction system that senses vancomycin and switches on expression of the vanRS and vanHAX genes
73
What is an overview of vanHAX?
vanHAX encode enzymes which change the D-Ala-D-Ala dipeptide in cell wall precursors to D-Ala-D-Lac which vancomycin no longer recognises, thus conferring resistance on bacteria carrying these genes.
74
What are treatment options to combat antibiotic resistance?
Novel antibiotics Novel treatments (Phage therapy and New drug combinations)
75
What is an overview of Daptomycin?
The treatment of complicated skin and skin structure infections caused by certain gram-positive infections and for bloodstream infections, including right-sided infective endocarditis, caused by S. aureus.
76
What is an overview of daptomycin mechanism of action?
Irreversibly binds to cell membrane of Gram-positive bacteria by calcium-dependent membrane insertion of molecule Rapidly depolarizes the cell membrane leading to efflux of potassium and destroys ion-concentrationgradient
77
What is unique about daptomycin?
New drug class (lipopeptide) Rapidly bactericidal New mechanism of action: acts by binding to cell membrane and disrupting the cell membrane potential No cross resistance
78
What is a problem with daptomycin?
Daptomycin is also made by Streptomyces and a recent study showed that resistance to daptomycin is widespread in soil bacteria
79
What is an overview of daptomycin resistance?
resistance in Gram-positive bacteria is uncommon, there are increasing reports of daptomycin resistance in Staphylococcus aureus, Enterococcus faecium and Enterococcus faecalis.
80
What is the contect for daptomycin resistance?
Such resistance is seen largely in the context of prolonged treatment courses and infections with high bacterial burdens, but may occur in the absence of prior daptomycin exposure.
81
What are healthcare strategies for reducing AMR?
Contain emerging threats through early detection with agressive response Infection preventin in non-hospital settings such as longtemr care facilities Stopping spread within and between healthcare facilities
82
What are community strategies for reducing AMR?
Widespread use of vaccines Prevention mechanisms - safe sex, safe food handling and screenings Improve antibiotic use
83
How have AMR deaths in communit and hospitals changed overtime?
18% reduction in deahts since 2013 and 28% in hospital acquired 41% decrease in Vancomycin-res Enterococcus and 25% decrease in drug resistant Candida Still 2.8 million infections a year and 35 thousands deaths 124% increase in Drug-resisitance Neisseria gonorrhea
84

3s2: Infection and Immunity (12 decks)

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