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BMS2052 > Antibiotics > Flashcards

Antibiotics Flashcards

1
Q

History of Antimicrobial agents

A

Prior to the 20th century, very few antimicrobials were available.
We were basically restricted to plant extracts and chemicals.

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2
Q

Examples of early antimicrobials

A

Mercury and Quinine

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3
Q

Quinine

A

Derived from the bark of Cinchona tree
Stops mosquitoes from biting someone so was used to treat malaria
Responsible for the funny taste in tonic water
Worked really well but we stopped using it because the malarial parasites became resistant to it

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4
Q

Mercury

A

Used to treat syphillis and other skin conditions
Mercury killed the infectious agent so it cured the disease but it was also quite toxic to humans so it is no longer in use

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5
Q

What intervention contributed to reduction in the burden of disease between 1900s and 2000 the most?

A

Sanitation.
Vaccines and antibiotics also contributed to this reduction, but improvements in sanitation had the most significant effect.
Scientists figured out that they needed to separate the drinking water from sewerage so that our drinking water would be free from contamination by disease causing agents
It is always better to prevent infections than treat it

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6
Q

What was the first drug available?

A

Salvarsan - used against the infectious agent that causes syphillis

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7
Q

How was Salvarsan discovered

A

Hata and Elhrich in the 1900s - Discovered that the dye Trypan red could kill trypanosomes - lead them to think of making derivates of this dye to kill particular microbes

  • They undertook a systematic synthesis of chemical variants of trypan red, which gave rise to compound 606 which could kill treponema pallidum (causative agent of syphilis). Compound 60, a sulfanilamide, was the first chemical known to target and kill pathogen causing syphillis.
    • By 1910, compound 606 was known as Salvarsan - first drug available on the market
    • Mode of action of Salvarsan wasn’t discovered for a long time
    • The concept for antibiotics is that it may not matter if we don’t know what exactly it is or what it does , because as long as it’s safe and works it can be a treatment
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8
Q

How was Penicilin discovered?

A

Alexander Fleming in 1928 discovered penicillin
- (was doing an experiment one day and put his culture near the window, forgot to take it out and went on holiday for 2 weeks - when he came back, his plate, which should have been growing Staph. Aureus, had a fungal contaminant - noticed that this fungus had inhibited S. aureus growth in some places on the plate)

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9
Q

When was large scale production of antibiotics made possible?

A

1942 by Howard Florey and Ernst Chain - due to the increase in demand for antibiotics as a result of World War

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10
Q

The Golden Age of Antibiotics

A

Was between the 1940s and 1950s.
Once we discovered certain fungi and bacteria could produce substances that could kill another bacteria, we could screen them for new antibiotics
Many other antibiotics and antimicrobial agents were developed during this time such as streptomycin,
Production of drugs declined by 1950s.,

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11
Q

What is an antibiotic

A

Describes any substance produced by microorganisms that is antagonistic to the growth of another microorganism in high dilution - antibiotics are not produced in labs

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12
Q

Selective toxicity

A
  • Any antimicrobial agent needs to target a biochemical process occurring in the pathogen but not in the host
    • Therefore, we normally target biochemical processes that are only in the microbes
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13
Q

Example of selective toxicity

A

penicillin targets biosynthesis of peptidoglycan in the bacterial cell wall (peptidoglycan doesn’t exist in humans or mammalian cells, so this antibiotic has no toxicity in humans)

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14
Q

Narrow Spectrum antibiotics

A

Drug itself only works against a limited number of bacteria (specific for a particular species)

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15
Q

Broad Spectrum Antibiotics

A
  • Work against tons of different types of bacteria

Penicillin is a broad spectrum antibiotic because most bacteria have a peptidoglycan cell wall

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16
Q

Antibiotics can be —, —-, —-

A

natural, semisynthetic, synthetic products

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17
Q

Natural antibiotics

A
  • Made by the fermentation of fungi or bacteria
    • Purify the drug from the culture
      e. g. penicillin, polyenes
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18
Q

Semi synthetic product

A
  • Chemical modifications of the natural product from fungi or bacteria
    • E.g. beta lactams
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19
Q

Synthetic products

A
  • Chemically synthesised in a lab and not produced by a microbe
    • Rare, nature is far better at producing antibiotics
      e. g. quinolones
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20
Q

Bacteriostatic antibiotics

A

Stops bacterial replication and growth, but do not kill the bacteria. Allows time for the adaptive immune response to launch and fight the infection.

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21
Q

Bactericidal antibiotics

A

Kills bacteria, given to patients that are immunocompromised and don’t have an effective immune system

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22
Q

Same antibiotic can be bacteriostatic for one bacteria, but bactericidal for another. True or False?

A

True

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23
Q

What are some common targets that antibiotics can bind to

A
  • Macromolecules such an enzyme that is unique to the microbe or highly divergent from human homologue
  • Metabolic processes in the microbes that aren’t in humans or can be bypassed in humans (e.g. folate is essential to all living cells. Humans can eat folate so if we turn off our folate synthesis pathway using a drug, we can make sure that the person getting the antibiotic is still getting folate through other sources such as our diet)
  • Target enzyme to be involved in microbial replication, growth or virulence (encodes toxins) so if it’s turned off, the microbe will die or will no longer cause disease
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24
Q

What are some recent antibiotic targets we are looking at?

A

-If drug target is only found in the microbe, the drug will only bind to the microbe and it won’t bind somewhere else and cause toxic effects in humans
Since we’re running out of targets nowadays, we are starting to look at enzymes that do have human homologues - might look slightly different or do something different that separates it from the human homologue and we exploit that in our new drugs

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25
Q

What is the most common antibiotic?

A

Ones that inhibit cell wall synthesis

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26
Q

Peptidoglycan

A
  • Key structural component of bacterial cell walls
    • Complex structure
    • Basic repeating unit is alternating sugars GlcNAc and MurNAc which continue along in a chain
    • From every MurNAc there is a stem peptide (amino acids attached to this sugar molecule of murNAc)
    • The stem peptide of the two peptidoglycan polymers join together through an interpeptide bridge
    • At the bottom of the stem peptide, can see D-Ala D-Ala amino acid sequence which is in all peptidoglycans and is important for some antibiotics
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27
Q

How is peptidoglycan made

A
  • Different enzymes start build different components of peptidoglycan
    • First, stem peptide starts getting made and is extended off MurNAc. Then a lipid tail is made so peptidoglycan can embed itself into the membrane. Then connect the alternating sugar GlcNAc to MurNac. Then, The interpeptide bridge amino acids start to get attached to the stem peptide. At a particular point when the peptide bridges and stems are built, the entire Lipid II unit translocates (flips) from the inside of the bacteria to the outside of the bacterial cell wall. At this point they still appear as a monomeric unit, and this is where the penicillin binding proteins have a role.
28
Q

Penicillin binding proteins

A
  • Large family of enzymes
    • They are the reason peptidoglycan can grow beyond its monomer and form the large complex structure that is the bacterial cell wall
29
Q

Role of penicillin binding proteins in peptidoglycan synthesis

A
  • Involved in trans-glycosylation (sticking the sugars together) to make the glycan chain
    • They are also involved in transpeptidation which is sticking the interpeptide bridges together
    • Can also cleave interpeptide bridges and stem peptides to breakdown peptidoglycan if bacteria wants to remodel during a certain stage of the lifecycle
30
Q

How do penicillin binding proteins recognize peptidoglycan

A

BPs is the recognition and binding to the D-Ala D-Ala amino acids on the bottom of the MurNAc stem peptides (this is basically their substrate that they need to bind to for peptidoglycan synthesis and remodelling
- Interfering with the ability of PBPs to recognise and bind to D-Ala D-Ala disrupts cell wall synthesis
PBPs are the major antibacterial targets for any antibiotic that has a Beta-lactam ring which mimics the structure of D-Ala D-Ala amino acids -they look similar in chemical space- thus Beta-lactams will bind into the same spot on PBPs thus preventing the PBP from binding to D-Ala D-Ala and inactivating PBP

31
Q

Beta-lactam rings

A
  • Mimic D-ala D-ala structure
  • Have different affinities for different PBPs (hence the different effects of beta lactams on different bacteria who all use different PBP from each other)
    • Most of the time, they are bactericidal for actively growing cells (because they can’t survive without their cell walls)
    • Some bacteria develop resistance against them through production of beta lactamase enzymes or PBP mutations which alter the way they bind to D-Ala D-Ala
32
Q

Beta lactam antibiotics

A
  • Have the beta lactam ring (pink square) and a 5 or 6 membered aromatic (blue) attached to the ring
    • Bactericidal and broad spectru,
    • Don’t require going to hospital, infected individuals can take at home- oral delivery
33
Q

Mode of action of beta Lactams

A
  • Inhibit growing bacteria; since the PBPs aren’t working well and the peptidoglycan isn’t being made, the bacteria grows bigger and wants to divide but doesn’t have enough peptidoglycan to split into two so it bursts and dies over time
    • When the cell wanted to divide, it needed new peptidoglycan to allow it to separate into 2, but if peptidoglycan production or cross linking is blocked by the beta lactams, it induces a futile cycle of peptidoglycan turnover and deregulates autolytic activities (the cell can’t hold up against turgor and osmotic pressure without new peptidoglycan so bacteria bursts)
34
Q

Glycopeptide antibiotics

A
  • Drug itself binds to the D-Ala D-Ala on the stem peptide (drug wraps itself around D-ala D-ala- meaning the PBPs can’t bind onto D-Ala D-Ala (inhibits peptidoglycan transpeptidation)
    • Is bactericidal because it interferes with cell wall synthesis
    • Is an incredibly complex chemical to deliver to humans and it’s thought not to get across membranes as easily as the smaller compounds - therefore is mainly used in infections caused by gram positive bacteria resistant to beta lactams
      Used as last resort (kept to hospitals and more serious infections) eg MRSA
35
Q

Example of glycopeptide antibiotic

A

Vancomycin

36
Q

Example of beta lactam antibiotic

A

Penicillin

37
Q

Antibiotics that inhibit protein synthesis

A

Still display selective toxicity because there are differences between human protein synthesis and bacterial protein synthesis
Includes antibiotics that bind to 30s subunit (block decoding of mRNA and amino acyl transferases)
Includes antibiotics that bind to 50s subunit (exit channel blockers and inhibit peptidyl transferases)
Are generally bacteriostatic with some exceptions because turning off protein synthesis in bacteria doesn’t kill them

38
Q

Example of 30S subunit antibiotic

A

Tetracycline, Aminoglycosides

39
Q

Example of 50s subunit antibiotic

A

Macrolides, Oxazolidinones

40
Q

Tetracycline

A

Binds to 30s subunit
Blocks the entry of amino acyl TRNA in to the A site
Bacteriostatic, broad spectrum, and orally available
Are a family of 4 member ringed compounds
Active against intracellular bacteria
Resistance developed through efflux of drug and ribosomal protection proteins

41
Q

Macrolides

A

Contain a 12-24 carbon lactone ring linked to one or more sugars
Bind reversibly to the 23 ribosomal RNA of the 50s subunit in the peptidyl transferase domain
Block the movement of amino acyl tRNA from the A site to the P site, thereby inhibiting peptide chain elongation
Oral, bacteriostatic, broad spectrum against gram positives
Can enter and accumulate inside eukaryotic cells so can also be used against intracellular pathogens such as Legionella
Resistance developed to it through efflux, RNA methylation (target modification) and modifying enzymes

42
Q

Oxazolidinones

A

Fully synthetic and new
Bind to rRNA on the A side of the peptidyl transferase center of the 50s subunit of ribosome
Bacteriostatic , orally available
Works against gram positives and M.tuberculosis
Used against bacteria that display resistance to multiple anitbiotics
Bacteria develop resistance to it through rRNA mutations

43
Q

DNA replication inhibitors

A

Fluroquinolones

44
Q

Fluroquinolones

A

Fully synthetic
Have a quinolone ring
Bind to DNA gyrase and topoisomerases, blocking formation of complex with nicked DNA
- Block DNA replication and DNA repair
- Bactericidal (because DNA replication is important to bacteria survival) and orally available
- Have broad spectrum activity
Usually used for urinary tract infections

45
Q

Transcription inhibitors

A

Stop bacteria from making mRNA, is bactericidal

Include Rifamycins, Fidaxomicin

46
Q

Rifamycin

A

Semi synthetic
Bactericidal, broad spectrum
Well absorbed orally and distributed well throughout the body
Can cross blood brain barrier
Reserved for infections that can disseminate into the brain such as Meningococcal

47
Q

Fidaxomicin

A

Natural
Not orally available
Used for C.difficile infections

48
Q

Antiviral agents

A

Target key steps in viral lifecyle

49
Q

Possible targets for antiviral agents

A

Block attachment of virus to host receptor
Prevent uncoating of virus and release of genome once inside host cell
Target nucleic acid synthesis through non-nucleoside reverse transcriptase inhibitors and nucleoside reverse transcriptase inhibitors
Can also be used against viral protein synthesis and protein processing (which is how virus makes many polypeptides from small genome)
Can also block release of virus from the infected cell such as neuraminidase inhibitors

50
Q

Antifungal agents

A

Challenging to develop as fungal cells are eukaryotic and share lots of similarities with human cells
There are some differences such as the composition of the cell membrane and cell wall and these are targeted
Fungal cells have ergosterol

51
Q

Antifungal agents

A

Challenging to develop as fungal cells are eukaryotic and share lots of similarities with human cells
There are some differences such as the composition of the cell membrane and cell wall and these are targeted
Fungal cells have ergosterol in their membrane unlike humans and this ergosterol is essential to membrane function - antibiotics developed to block ergosterol synthesis and also bind to ergosterol - Fluconazole and amphotericin B
Fungal cell wall is composed of chitin and mannose and B, 1 6 and B 1,3 glucans in between chitin and mannose - can block synthesis of these glucans - Caspofungin
Can also inhibit DNA/RNA synthesis in cell through thymidine analogues such as flucytosine
Resistance through mutations/modifications to target, efflux and altered prodrug activation

52
Q

Antibiotic resistance

A

When you fail to treat at infection at the recommended dose- might have to go back for a second or third dose
of the antibiotic that should have treated your infection with the first dose - if the antibiotic doesnt kill the bacteria or stop the growth of bacteria at the recommended dosage then bacteria is resistant

53
Q

Burden of Antibiotic Resistance

A

Is a creeping problem - places significant burden on healthcare systems and society
Drug resistant infections in hospitals are increasing
Community infections are on the rise - drug resistant bacteria are no longer confined to just hospitals
There are some strains that are resistant to all available antibiotics, is a problem as drug production has declined

54
Q

How do bacteria acquire resistance:

A
  • Chromosomal mutation that produces a drug resistant target ; allows the bacterial cell to become resistant and multiply until the mutation becomes the dominant form- the mutation is now present in all bacterial cells - can occur in a very short period of time in presence of high concentration of antibiotics
    Ø Resistance genes on plasmids:
    • Resistance genes carried on plasmids can spread from one cell to another rapidly (horizontal gene transfer)
      Ø Resistance genes on transposable genetic elements:
    • Resistance genes on transposable genetic elements can move between both plasmids and the chromosome, allowing for even greater dissemination
55
Q

What are the 3 types of resistance

A

Intrinsic resistance, acquired resistance, and tolerance, a

56
Q

Intrinsic resistance

A

Resistance is naturally in the bacteria

- Lack susceptible target (might not produce the enzyme the antibiotic binds to) 
- May be impermeable to the drug, or may be influx/efflux problems eg vancomycin cant be used to treat gram negative bacteria as vancomycin cant access cytoplasm of gram negative bacteria
- May have a natural, preexisting modifying enzyme that changes the antibiotic so that it can't work
57
Q

Acquired resistance

A
  • Through spontaneous mutations (e.g. change to target binding site where antibody binds)
    • Through acquiring resistance genes
58
Q

Tolerance

A
  • The bacteria are inhibited but don’t become unviable and recover after antibiotic disappears
    bacteria might slow down a bit and might not grow as well but they don’t die, and as soon as antibiotic is removed they continue growing)
    • Problem because you can’t keep people on antibiotics forever
59
Q

Spontaneous mutations

A

Aquired resistance - spontaneous mutations:

- Mutation in chromosome 
- Rare because DNA errors are rare in bacteria 
- Usually confers resistance to a single class of antibiotics 
- Usually changes antimicrobial target site, a modifying enzyme or an efflux system 
- Cross-resistance to structurally related compounds only (only compounds that look pretty similar and work by the same mechanism will also be resistant - therefore only single class of antibiotics. 
- A single target mutation may be enough to generate resistance, but some bacteria need to acquire a series of mutations to enable resistance - trimethoprim, rifamycin - single, penicillin - multiple as there are multiple penicillin binding proteins
60
Q

Resistance genes on plasmids

A
  • There is a resistance gene pool in the environment
  • The resistance genes in these gene pool are produced by antibiotic producing organisms ( so these organisms don’t die from the antibiotic that they produce)
  • Resistance gene spread through population by a plasmid via horizontal gene transfer (can even cross different species)
  • Resistance gene pool under selection pressure and constantly evolving due to antibiotics usage
  • Plasmids carrying resistance genes confer resistance to unrelated class of antibiotics
61
Q

Plasmid R100

A
  • Plasmid R100 contains a tetracycline resistance cassette that was encoded on a transposon- the transposon had jumped onto the plasmid
    • There was another transposon that had also jumped into this same plasmid, with a chloramphenicol resistance gene and within this transposon was another transposon and 2 other transposons within that and all of these transposons carried resistance to different types of antibiotics
    • Plasmid R100 with all these transposons has moved through bacteria and our environment, making the bacteria resistant to multiple classes of antibiotics
62
Q

Modification or inactivation of the antibiotic

A

Modification or inactivation of the antibiotic:
- Bacteria can actually damage the chemical itself (modify the drug so that it no longer works)

1. Inactive drug by chemically cleaving it: 
- This is what the beta lactamases do (cleave penicillins and cephalosporins)  They chop the beta lactam square ring and open it up, changing its chemical shape meaning they can no longer bind to PBPs with same affinity - Example is TEM-3 
2. Inactivate drug by adding chemical moieties: 
- This is how bacteria get around vancomycin Aminoglycoside modifying enzymes  change the aminoglycosides, which change the affinity of the antibiotic to its target, makes it bind with less affinity to target and not work as well
63
Q

Modify antibiotic transport

A
  1. Modify antibiotic transport:
    • Decrease ability of drug to get through cell wall (decreases permeability), if drug can’t get inside cell it won’t work
      Can actively pump drug back out of cell, meaning dose inside cell is not high enough to have an effect

Decreased cell wall permeability:

- To do this, some bacteria can alter the porin or outer membrane Omp proteins which lead to a decreased uptake of beta lactam antibiotics in some bacteria - K.pneumonia and P.aeuroginosa
- Basically blocking gates of entry for the antibiotic

Increased efflux from cell:
- Efflux meaning pump out
- Many resistant bacteria have acquired specific efflux pump mechanisms to specifically export antibiotics from cell
Means intracellular concentration is never high enough for drug to work
- Have efflux for tetracyline

64
Q

Modification of target site

A
  • It’s also possible that there is changes to the binding site of the target to lower the affinity and protect it from antibiotic binding (modification of target site)
    • Macrolides like erythromycin block protein synthesis by binding to the rRNA in 50S ribosomal subunit, blocking chain elongation
    • Erm enzymes methylate the residue on the RNA where erythromycin binds, meaning erythromycin can’t bind to the RNA with the same affinity so doesn’t work well (modification of target site)
65
Q

Enterobacteriacae

A
  • A large family of gram negative bacteria with many pathogens in the family including klebsiella pneumoniae
    • Carbapenem resistant Enterobacteriaceae are a serious problem for clinicians
66
Q

Carbapenems

A

Are Beta lactam antibiotics (derivatives of penicillin)
Can inhibit Beta lactamase
- More broad spectrum than penicillin and cephalosporins (can treat more things because they can inhibit beta lactamases)
- Were preferred treatment for Enterobacteriaceae, (became a drug of last resort) because the penicillin alone doesn’t work very well
- Molecule thienamycin was discovered from the animal pathogen streptomyces cattleya ; thienamycin was found to be a beta lactamase inhibitor
- Thienamycin could be used to prevent beta lactamase activity so penicillin could be effective
Thienamycin was the first carbapenem

67
Q

First case of Carbapenem resistance

A

Arose in North Carolina
K.pneumonia produced an enzyme called KPC - enzyme that chops up carbapenems
KPC is encoded by the blaKPC gene, which is located within a Tn-3 like transposon on a plasmid
Not only do you get the plasmid spreading to different bacteria but the transposon could also move itself onto the bacterial chromosome and cause stable horizontal gene transfer)

BMS2052 (8 decks)

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