W11.1_Antimicrobial Targets

Question 1

Explain the selective toxicity of antimicrobials. What are the key target sites of antimicrobials?

Answer 1

• Ability to suppress/kill infecting microbes without injury to host
• ∵ Structural differences of eukaryotes and prokaryotes
• Drug accumulation in microbes at higher level
• Specific action of drug -> cellular structures/biochemical processes unique to/more harmful in it
• Key target sites: cell wall, protein and nucleic acid synthesis/cell membrane functioning/essential metabolite production

Question 2

In terms of cell wall synthesis, describe the properties and structure of gram positive and gram negative bacterial cell wall. Explain how it impacts the efficiency of different antimicrobials.

Answer 2

• Bacterial cell wall: determines cell shape, rigid to give mechanical strength, metabolically inert
• Carboxylate (NAM + NAG) + peptide chains -> peptidoglycan (unique)
• Gram stain: reflects cell wall structure (+ve purple, -ve red)
• +ve: peptidoglycan + cell membrane + cytoplasm
• -ve: outer membrane + periplasm + peptidoglycan + cell membrane + cytoplasm
• ∴ -ve: drug has to penetrate outer membrane + periplasm -> tailor-made drugs needed

Question 3

Explain the structure of peptidoglycan how it is synthesised and grown. State how penicillins, bacitracin, and vancomycin work.

Answer 3

• Peptidoglycan: only DAP and D-proteins exist naturally in bacteria, pentapeptides always linked to NAM
• Synthesis and growth of peptidoglycan: losing D-ala end residue -> interbridge bonding (usually penta-glycine) forms between Meso-DAP and D-ala
• ex. ß-lactams (penicillins): prevent enzymatic loss of D-ala residues in transpeptidase reaction site
• ex. bacitracin: prevents new NAM crossing cell membrane
• ex. vancomycin: blocks binding site

Question 4

In terms of protein synthesis, explain how it relates to selective toxicity. State how tetracycline, erythromycin, chloramphenicol, lincosamides, and aminoglycosides work.

Answer 4

• Prokaryotic ribosomes: 30s + 50s = 70s (s = size)
• Eukaryotic ribosomes: 40s + 60s = 80s (overlapping of subunits causes smaller total sizes)
• ∵ Different sizes -> antimicrobials don’t fit in human cells
• ex. tetracycline: blocks binding of tRNA (30s)
• ex. erythromycin: inhibits translocation (50s)
• ex. chloramphenicol, lincosamides: inhibit transpeptidation
• ex. aminoglycosides: inhibits proofreading and initiation

Question 5

In terms of nucleic acid synthesis, cell membrane functioning, and essential metabolite production, explain how quinolones, fluoroquinolones, rifamycins, polymyxin, sulfonamides, and trimethoprim work.

Answer 5

• Nucleic acid synthesis
• DNA in bacteria: circular, closed, supercoiled -> essential, as housekeeping genes
• ex. quinolones, fluoroquinolones: prevents DNA gyrase from operating that aids supercoiling function
• ex. rifamycins: bind strongly to RNA polymerase
• Cell membrane functioning
• ex. polymyxin: targets energy metabolism in gram negative cell membrane -> hydrophobic tail acts as detergent to cause membrane damage
• Essential metabolite production (ex. bacterial folic acid)
• ex. sulfonamides: competitive inhibitors of DHPS to prevent conversion of PABA to DHF
• ex. trimethoprim: binds to DHFR to prevent reduction of DHF to THF

Question 6

Explain the general aim of antifungals. What are common targets of antifungals?

Answer 6

• Fungi are eukaryotes, most of their cellular machinery is same to human cells
• ∴ Antifungals are topical, with few drugs targeting unique metabolic processes in fungi
• Targets:
• Cell wall synthesis: polyoxins inhibit chitin synthesis, echinocandins inhibit glucan synthesis
• Membrane functions: polyenes bind to ergosterol, disrupt membrane integrity
• Ergosterol synthesis: azoles and allylamines inhibit it
• Nucleic acid synthesis: 5-fluorocytosine is a nucleotide analog that inhibits nucleic acid synthesis
• Microtubule formation: griseofulvin disrupts microtubule aggregation during mitosis

Question 7

Describe how future treatments of antimicrobials may help society.

Answer 7

• Future treatments: computers designing molecules to interact specific microbial structures, new methods of screening natural products, drug combinations, bacteriophage therapy