Antibiotics

Question 1

Uses of antibiotics

Answer 1

• Drugs used to treat bacterial infections
• Widely used and misused drugs
• In hospitals, they acquire 30% of the drug budget
• 80% of human use in the community:
  
  • > 50% is for respiratory infections
  • > 15% is for urinary tract infections

Question 2

What are antibiotics?

Answer 2

• Natural products: fungi and bacteria that live in the soil dwellers.
• These organisms are used to coexisting with other microorganisms, so they developed mechanisms which produce compounds that inhibit the growth of other microorganisms.
• Able to collect these products by fermentation and then chemically modify them, so they are more suitable for pharmacological properties.

Question 3

How are scientists able to get antibiotics? What do they do to antibiotics?

Answer 3

Scientists are able to collect these products by fermentation and then chemically modify them, so they are more suitable for pharmacological use:

• They increase their pharmacological properties
• They increase their antimicrobial effect
• Need to make sure they are not toxic, not metabolised too quickly and doesn’t bind protein in the blood so it can be free in the blood - this reduces the dose.

Question 4

Example of synthetic antibiotics

Answer 4

Most antibiotics are derived from natural products, some are totally synthetic such as sulphonamides

Question 5

Discovery of antibiotic penicilin

Answer 5

• Alexander Fleming’s original culture of Staphylococcus aureus was contaminated with penicillium notatum
• Diffusion of the penicillin into agar caused lysis of the bacteria
• This lead to the discovery of the antibiotic penicillin

Question 6

Priniciples of antibiotics as therapeutic agents

Answer 6

• Selective toxicity

- Therapeutic margin

Question 7

Selective toxicity of antibiotics

Answer 7

• This means the antibiotic should be able to kill the bacteria without harming the host cells.
• This is able to happen because bacteria and human cells have different structures, an antibiotic can be made to target the cell wall of a bacteria so not to harm the host.
• More difficult in anti-viral because viruses are intracellular hosts which means they integrate within the human genome.

Question 8

Therapeutic margin of antibiotics

Answer 8

• This is the balance of the antibiotic between being sufficient at treating the bacterial infection and becoming toxic to the host.
• It is the active dose which is the MIC (minimum inhibitory concentration) which is the concentration needed to see an active effect of the drug.
• Some antibiotics are safe so you can increase the dose by a lot and no toxic effect will be seen, however some antibiotics are very toxic so the MIC and toxic dose are very close.
• When a drug is described as being safe it means, they have a wide therapeutic effect and vice versa.

Question 9

How do antibiotics disturb the natural flora?

Answer 9

• The natural flora is maintained because each microbe keeps the other one in balance by producing something that inhibits the growth of another.
• e.g. in the gut - when the balance is disturbed, this is when disease occurs because one microbe grows to form colonies.
• For example Clindamycine and broad spectrum beta lactams are used leading to the overgrowth of C. dif which is a gram +ve spore forming bacteria, leading to diarrhoea, ulceration and inflammation.

Question 10

How are antibiotics classified?

Answer 10

• By type of activity
• Structure
• Target site of activity

Question 11

What are the types activity of antibiotics?

Answer 11

Used in different scenarios -

• Bacteriostatic: inhibit the bacteria from growing e.g. when a patient is not immunocompromised and there not used for emergency use. Need a higher dose to be able to kill the bacteria (toxic dose)
• Bacteriocidic: actively kills the bacteria e.g. used when a patient is immunocompromised and therefore can be used for emergency, the MIC and the toxic dose are very close and therefore it can be used to kill the bacteria.

Question 12

How does the structure of antibiotics effect?

Answer 12

• Some antibiotics have specific structures, which help them target the bacteria they are killing
• E.g. beta lactams antibiotics have a beta lactam ring in their structure which means they are able to act as competitive substrates for the enzymes involved in the bacterial cell wall.
• Therefore, when a bacteria is resistance, it means they have enzymes which are able to breakdown the beta lactam ring in the antibiotic so it no longer has a therapeutic effect.

Question 13

Broad specturm antibiotics

Answer 13

Able to work on multiple different bacteria and overuse of this means resistance can occur

Question 14

Narrow spectrum

Answer 14

• Antibiotics that can only work on certain bacteria and therefore need to know what bacterial infection it is to administer the drug.

Question 15

Cephalosporins

Answer 15

Generation of modified antibiotics each with a different chemical modification which is suited to certain types of bacteria
The modification target different types of bacteria, due to different types of bacteria having different structures

Question 16

What are the 6 types of bacterial targets for current antibiotics?

Answer 16

• Cell wall synthesis inhibitors
• Protein synthesis inhibitors
• DNA/RNA synthesis inhibitors
• Folic acid metabolism inhibitors
• Cell membrane damaging
• Free radicals generators

Question 17

Cell wall synthesis inhibitors include examples

Answer 17

• Beta lactams and vancomycin

- Inhibit the cell wall formation which means bacteria will die and cleared off by the immune system

Question 18

Protein synthesis inhibitors include examples

Answer 18

Erythymocyin and Chloamephicnal

• Bind to the ribososome in different places and inhibit protein synthesis.
• Does damage the host protein synthesis because there is different in the bacterial ribosomes and the host ribosomes

Question 19

DNA/RNA synthesis inhibitors

Answer 19

Rifamocin and Quinolone

• Inhibit certain enzymes which are only specific to the bacteria:
  
  • > DNA gyrase which is needed for coiling and uncoiling when the genome is the replicating
  • > DNA directed RNA polymerase which inhibits RNA making
• This type of antibiotics is used to stop the spread of community acquired meningitis and TB

Question 20

Folic acid metabolism inhibitors

Answer 20

Trimetrhoprim and Sulfoamides

• Folic acid is a co-factor for enzymes which are essential in both bacteria and host, however, host doesn’t synthesise folic acid in the body, it is consumed whereas bacteria synthesises it.
• Therefore, these antibiotics inhibit the bacteria from making folic acid meaning they are not able to function properly which means they die.
• These also have good selective toxicity

Question 21

Cell membrane damaging

Answer 21

Colistin

• Most toxic to the host because both the bacteria and the host have cell membranes.
• Only used on bacteria which is resistant to other antibiotics such as gram -ve E. coli

Question 22

Free radical generators

Answer 22

Nitrofurantoin

• Free radicals are toxic in the bacteria and therefore anaerobic bacteria are usually treated with this.
• Typically used to treat UTI because it is not toxic and most of the drug goes to the kidney which is the site of infection.

Question 23

Gram +ve bacteria

Answer 23

• Contain a large peptidoglycan: cross-linking structure that sits on the top of the membrane and contains components of the bacteria cell wall.
• Antibiotics that target the cell wall synthesis work on enzymes which are involved in making the peptidoglycan
• These are present in the area between the membrane the peptidoglycan which is a highly porous structure and therefore the antibiotics can easily access this area.

Question 24

Gram -ve bacteria

Answer 24

• Contains inner membrane, periplasmic space containing peptidoglycan and outer membrane
• Outer membrane is very impermeable and requires pores for the antibiotic to cross the periplasmic space.
• It is easier to treat gram +ve bacteria compared to gram -ve bacteria.

Question 25

Structure of peptidoglycan

Answer 25

• made of pentapeptides which are cross linked together.
• They hold the matrix together which has a long polysaccharide chain
• This is put together by a series of enzymes
• Different bacteria have different peptidoglycan and therefore not all antibiotics will work on all bacteria.

Question 26

How to synthesise peptidoglycan?

Answer 26

Need: 2 disaccharides and 5 peptides, the last 2 peptide are D-ala.

1. D-ala molecule is transported across the membrane by linking a lipid transport molecule.
2. Once it crosses the membrane, it gets attached to a 5 amino acid by enzymes which remove the D-ala D-ala sequence, leading to the structure being polymerised to the cell wall.
3. The transcarboxypeptidase enzyme which is found in the bacteria cell wall does that.

Question 27

How do beta lactams work in gram +ve bacteria?

Answer 27

• Work on the enzyme - transcarboxypeptidase enzyme that makes the peptidoglycan and affects the cross-linking structure.
• Vancomyocin is able to attach to the terminal D-ala which means the enzyme does not cleave off.

Question 28

How do beta lactams work on Gram -ve bacteria?

Answer 28

• In the Gram -ve bacteria, the porin is needed to allow the beta lactam in through the outer membrane.
• Once it binds to the penicillin binding proteins (PBP) which are enzymes responsible for making the peptidoglycans; it inhibits the binding proteins meaning the cross-linking molecules are not able to occur and the wall is not formed.
• This triggers autolysis of the bacteria and hence why beta lactams are bactericides

Question 29

Action of sulphonamide

Answer 29

Blocks the enzyme competing with the natural substrate PABA.
This means the bacteria cannot make folic acid and dies.

Question 30

When are antibiotics used?

Answer 30

• treatment for bacterial infection
• Prophylaxis which means they prevent someone from getting the infection:
  
  • > This can be due to someone coming in contact with an infected person.
  • > Peri-operative gut surgery
  • > People who are immunocompromised

Question 31

What does the minimum inhibitory concentration (MIC) depend on?

Answer 31

• Host: age, weight, severity of infection, liver and kidney function
• Bacteria: susceptibility of the organism
• Antibiotic properties: toxicity