Bacterial Infection

Question 1

What are 5 main antibiotic target methods?

Answer 1

1. bacterial cell wall
2. bacterial cell membrane
3. DNA/RNA Synthesis
4. bacterial protein synthesis
5. bacterial folate synthesis

Question 2

Prokaryotes v eukaryotes

Answer 2

Prokaryote:
no nucleus, no organelles single celled, cell wall

Eukaryote
larger, more complex, nucleus and organelles, can be single/multi cellular

Both: DNA, ribosomes, cytoplasm, plasma membrane

Question 3

Gram positive v gram negative structure

Answer 3

1. Gram -ve has outer membrane and an inner membrane - good antibiotic target
2. gram positive has no outer membrane, teichoic acid, gram negative LPS (ubiquitous, causes massive inflammation, induces fever)

Question 4

Moa of beta lactams

Answer 4

normally during cell wall synthesis:
- transpeptidase (PBP) catalyses cross-links between adjacent peptide chains by removing terminal D-alanine
- this allows crosslinking of peptide chains
- strengthens cell wall integrity

action of beta lactams:
- beta-lactams bind tightly to AS of transpeptidase
- PBPs are inactive in cell wall
- cross linkage of peptidoglycan does not occur → less cell wall integrity → weak cell wall → over time destroyed + lyses

Question 5

How have beta lactams developed resistance?

Answer 5

By producing beta lactamase → this degrades beta lactam ring in abx → cannot exert bacteriocidal effects

Question 6

bacteriocidal v bacteriostatic

Answer 6

Bacteriocidal: kills bacteria

Bacteriostatic: prevents bacteria growth

Question 7

vancomycin moa - only gram + bacteria (eg MRSA)

Answer 7

• vancomycin binds to D-alanine terminal → inhibits glucosyltransferase and P-phospholipid carrier →prevents NAM and NAG synthesis within the peptidoglycan layer → weakens cell wall → leakage of intracellular components → cell death

Question 8

Which drug class targets cell membrane?

Answer 8

polymyxin (lipopeptide abx)

Question 9

What is moa of polymixin/colistin?

Answer 9

• heptapeptide ring of polymyxin binds to LPS layer of bacteria (gram -ve only)
• this binding displaces Ca2+ and Mg2+ ions which stabilise LPS
• ion disruption → outer membrane disruption
• also interferes w fatty acid chain → more polymyxins inserted into membrane → membrane permeability affected → allows passage of molecules inc hydrophobic compounds → this promotes polymyxin uptake

Question 10

Major side effect of polymyxin

Answer 10

• nephrotoxicity
• low renal excretion
• accumulates in renal tubular cells
• induces renal cell cycle arrest → apoptosis

Question 11

Why is polymyxin limited to gram negative bacteria?

Answer 11

• Gram-positive organisms lack outer membrane → naturally resistant to polymyxins

Question 12

Which drug class does vancomycin belong to?

Answer 12

Glycopeptide antibiotics

Question 13

how have bacteria developed abxr?

Answer 13

some bacteria produce beta-lactamase enzymes to degrade beta-lactam ring in abx

unable to exert bacteriocidal effects

Question 14

how to overcome abxr?

Answer 14

add isoxazole ring eg fluclox to acts as shield due to bulky side chain groups

prevents beta-lactamase produced by bacteria from accessing the beta-lactam ring

Question 15

why does polymixin only target gram - bacteria?

Answer 15

because it targets LPS which is only in gram neg, not gram pos

Question 16

what is a major side effect of polymixin?

Answer 16

nephrotoxicity → low renal excretion → reabsorption by renal tubular cells→ accumulates in renal cells → renal cell arrest

Question 17

why is spectrum of polymyxin limited to gram-negative organisms?

Answer 17

• Gram-positive organismslack an outer membraneand are thus naturally resistant to polymyxins
• The synthesis of new molecules that are less toxic and have greater activity than conventional antibiotics is challenging

Question 18

The P450 enzyme CYP2C8 is inhibited by trimethoprim. What would happen to drugs that are normally metabolised by CYP2C8 (such as warfarin) if given alongside trimethoprim?

Answer 18

trimethoprim decreases excretion rate of warfarin

higher serum level

higher risk of haemorrhage

Question 19

Sulphonamides also target bacterial folate synthesis. What is their mode of action?

Answer 19

• sulfonamides bacteriostatic (stops bacteria growth)
• antagonist for PABA (folate substrate)
• binds and inhibits dihydropteroate synthase
• therefore dihydrofolatic acid not produced
• therefore bacteria cannot replicate

Question 20

Trimethoprim moa?

Answer 20

PABA → dihydropteroic acid → dihydrofolatic acid → tetrahydrofolate

dihydrofolate reductase converts dihydropteroic acid → dihydrofolatic acid

trimethoprim binds to dihydrofolate reductase → prevents folate production

bacteria needs folate for protein and nucleic acid synthesisn

without it cell dies

Question 21

Rifampicin moa

Answer 21

• inhibits bacterial RNA polymerase
• no DNA transcription - cell death

Question 22

why do we need abx prophylaxis?

Answer 22

• prevent an initial infection (primary)
• prevent the recurrence/ reactivation of an infection (secondary)
• prevent infection by eliminating a colonising organism
• however unnecessary abx use causes ABR

Question 23

when do we use prophylaxis Abx?

Answer 23

• immunocompromised (eg chemo, late stage hiv/AIDS)
• loss of spleen - eg during trauma injury - need abx prophylaxis for rest of life
• GI surgeries - high risk surgeries in terms of nosocomial infection
• cardiac procedures
• UTIs

Question 24

How effective is rifampicin as prophylactic?

Answer 24

Rifampicincan be used as monotherapy for a few days as prophylaxis against meningitis.

Still, resistance develops quickly during long-term treatment of active infections, so the drug is always used against active infections in combination with other antibiotics.

Question 25

mupirocin therapeutic effect and moa?

Answer 25

• used for skin infections (impetigo caused by S. Aureus)
• interferes with RNA synthesis
  • inhibits iseleucyl-tRNA synthetase
  • therefore bacterial protein synthesis inhibited