Antibiotics and antifungals

Question 1

How are bacteria classified?

Answer 1

Based on their membrane properties.
Gram positive bacteria: prominent peptidoglycan cell wall, e.g. Staphylococcus aureus.
Gram negative bacteria: outer membrane with lipopolysaccharide, e.g. Escherichia coli.
Mycolic bacteria: outer mycolic acid layer, e.g. Mycobacterium tuberculosis.

Question 2

What are the processes involved in nucleic acid synthesis in prokaryotic protein synthesis?

Answer 2

Dihydropteroate (DHOp) produced from paraaminobenzoate (PABA), catalysed by DHOp synthase.
Converted into dihydrofolate (DHF).
Tetrahydrofolate (THF) produced from DHF by DHF reductase.
THF → important in DNA synthesis.

Question 3

What are the processes involved in prokaryotic protein synthesis?

Answer 3

Nucleic acid synthesis.
DNA replication.
RNA synthesis.
Protein synthesis.

Question 4

What happens in DNA replication in prokaryotic protein synthesis?

Answer 4

DNA gyrase (topoisomerase) releases tension from DNA molecules.

Question 5

What happens in RNA synthesis in prokaryotic protein synthesis?

Answer 5

RNA polymerase produces RNA from DNA template, differs from eukaryotic RNA polymerase.

Question 6

What happens in protein synthesis in prokaryotes?

Answer 6

Ribosomes produce protein from RNA templates, differ from eukaryotic ribosomes.

Question 7

What are the target molecules of antibiotics that are protein synthesis inhibitors?

Answer 7

Nucleic acid synthesis: dihydropteroate (DHOp), tetrahydrofolate (THF).
DNA replication: DNA gyrase.
RNA synthesis: RNA polymerase.
Protein synthesis: ribosomes.

Question 8

Which antibiotics target the nucleic acid synthesis stage of prokaryotic protein synthesis?

Answer 8

Sulphonamides inhibit DHOp synthase.

Trimethoprim inhibits DHF reductase.

Question 9

Which antibiotics target the DNA replication stage of prokaryotic protein synthesis?

Answer 9

Fluoroquinolones (e.g. ciprofloxacin) inhibit DNA gyrase and topoisomerase IV.

Question 10

Which antibiotics target the RNA synthesis stage of prokaryotic protein synthesis?

Answer 10

The rifamycins (e.g. rifampicin) inhibit bacterial RNA polymerase.

Question 11

Which antibiotics target the protein synthesis of prokaryotes?

Answer 11

Ribosomes are inhibited by:
Aminoglycosides (e.g. gentamycin)
Chloramphenicol
*Macrolides (e.g. erythromycin)*
Tetracyclines

Question 12

What are the stages of bacterial wall synthesis?

Answer 12

Peptidoglycan synthesis.
Peptidoglycan transportation.
Peptidoglycan incorporation.

Question 13

What happens in peptidoglycan synthesis?

Answer 13

A pentapeptide is created in N-acetyl muramic acid (NAM).

N-acetyl glucosamine (NAG) associates with NAM, forming peptidoglycan.

Question 14

How is peptidoglycan transported?

Answer 14

Across the cell membrane by bactoprenol.

Question 15

How is the peptidoglycan incorporated in to the bacterial cell wall?

Answer 15

When transpeptidase enzyme cross-links peptidoglycan pentapeptides.

Question 16

What drugs target peptidoglycan synthesis?

Answer 16

Glycopeptides (e.g. vancomycin) bind to the pentapeptide, preventing peptidoglycan synthesis,

Question 17

Which drugs target peptidoglycan transportation?

Answer 17

Bacitracin inhibits bactoprenol regeneration, preventing peptidoglycan transportation.

Question 18

Which drugs target peptidoglycan incorporation?

Answer 18

Beta-lactams bind covalently to transpeptidase, inhibiting peptidoglycan incorporation into cell wall. Beta-lactams include carbapenems, cephalosporins and penicillins.

Question 19

Which drugs target bacterial cell wall stability?

Answer 19

Lipopeptide, e.g. daptomycin, disrupts Gram positive cell walls.
Polymyxins bind to LPS and disrupt Gram negative cell membranes.

Question 20

What are the causes of antibiotic resistance?

Answer 20

Unnecessary prescription- ~50% of antibiotic prescriptions not required.
Livestock farming- ~30% of UK antibiotic use in livestock farming.
Lack of regulation- OTC availability in Russia, China, India.
Lack of development- very few antibiotics in recent years.

Question 21

What are the different mechanisms of antibiotic resistance?

Answer 21

Production of destruction enzymes: beta lactamases hydrolyse C-N bond of the beta-lactam ring.
Additional target: different DHF reductase enzyme produced.
Hyperproduction: bacteria significantly increase levels of DHF reductase.
Alterations in drug permeation: reductions in aquaporins (drug influx) and increased efflux systems.
Enzyme alteration: mutations in DNA gyrase enzyme.

Question 22

How can fungal infections be classified?

Answer 22

In terms of tissues/organs:
Superficial- outermost layers of skin
Dermatophyte- skin, hair or nails
Subcutaneous- innermost skin layers
Systemic- primarily respiratory tract

Question 23

What are the 2 most common anti fungal drugs licensed in the UK?

Answer 23

Azoles, e.g. fluconazole.

Polyenes, e.g. amphotericin.

Question 24

Give examples of antibiotics that become resisted due to production of destruction enzymes.

Answer 24

Penicillins G & V → Gram positive.
Flucloxacillin and temocillin → beta-lactamase resistant.
Amoxicillin → broad spectrum, Gram negative activity, coadministered with clavulanic acid.

Question 25

Give an example of an antibiotic-resistant bacterium that becomes resistant due to additional targets being present.

Answer 25

E. coli produce different DHF reductase enzyme making them resistant to trimethoprim.

Question 26

Give an example of an antibiotic-resistant bacterium that becomes resistance due to an alteration in target enzymes.

Answer 26

S. aureus- mutations in the ParC region of topoisomerase IV confers resistance to quinolones.

Question 27

Give an example of an antibiotic-resistant bacterium that becomes resistant due to hyperproduction.

Answer 27

E. coli produce additional DHF reductase enzymes making trimethoprim less effective.

Question 28

Which bacteria are most likely to develop resistance to antibiotics by alteration in drug permeation?

Answer 28

Gram negative bacteria.

Question 29

What is the action of azoles?

Answer 29

Inhibit cytochrome P450-dependent enzymes involved in membrane sterol (e.g. ergosterol) synthesis.

Question 30

What are the indications for fluconazole (oral) treatment?

Answer 30

Candidiasis and systemic fungal infections.

Question 31

What is the action of polyenes?

Answer 31

Interact with cell membrane sterols (e.g. ergosterol), forming membrane channels (create pores).

Question 32

What are the indications for amphotericin (I-V) treatment?

Answer 32

Systemic fungal infections.