Lecture 9: Anti-infectives pt 2

Question 1

How to fight anti-microbial resistance(AMR)

Answer 1

Surveillance: Drug resistance bacteria can spread through human/community interactions and through produce/ environmental factors=complex issue

Infection prevention and control: take meds to keep drug level sufficiently high-prevent bacterial comeback

Stewardship

Research and innovation

Question 2

Antimycobacterial agents: TB

Answer 2

Initiated by the inhalation of aerosol droplets=like covid
Initial stage: innate immune response(recruitment of inflammatory cells to lung)
APCs present mycrobacterial antigens to prime T cells
Recruitment of T cells, B cells, activated macrophages etc. leads to establishment of granulomas containing pathogens-difficult for drugs to penetrate
Tissue damage
Transmission through coughing

Question 3

Rifamycin

Answer 3

TB treatment

Binds to beta-subunit of DNA-dependent RNA polymerase to suppress transcription and so inhibit proliferation= inhibit RNA synthesis by targeting RNA polymerase
Effective in macrophages

Bacteriocidal

Resistance due to chromosomal mutation changing binding site on polymerase

Question 4

Isoniazid

Answer 4

Mechanism: inhibit mycolic acid synthesis->inhibit cell wall synthesis
Effective in macrophages
Pro-drug: enters bacteria by diffusion, activated by KatG(a catalase-peroxidase)
Generates radicals which binds NAD+ and NADP+ inhibit enzymes for wall synthesis
ROS generated during drug activation also contributes to mycobactericidal effect
Resistance: increased efflux or mutation in KatG

TB

Question 5

Ethambutol

Answer 5

Mechanism: inhibits arabinosyl transferase II: essential enzyme in cell wall synthesis
Bacteriostatic
Only effective against mycobacteria
Resistance: enhanced efflux or changes in target enzymes

TB

Question 6

Pyrazinamide

Answer 6

Mechanism: disrupts membrane function
Necrotic granulomas effective
Produrg: diffuses into pathogen, activated to POA- by enzyme PncA
Resistance: mutation in PncA and decrease uptake

See pic

TB

Question 7

TB treatment strategy

Answer 7

First-line drugs: given together prevent resistance
RIPE: Rifampicin, isoniazid, pyrazinamide and ethambutol = 2months
Followed by isoniazid and rifampicin for an additional 4 months

Second-line drugs: mainly used for resistant strains
Streptomycin, cycloserine, fluoroquinolones

Question 8

Fungal infection pathology

Answer 8

Often associated with skin or mucous membranes
Systemic fungal disease are increasing in frequency due to widespread use of antibiotics
Kill bacteria that normally keep fungi under control

Question 9

4 Site of action of antifungal drugs

Answer 9

Membrane function: Amphotericin B
Cell wall synthesis: caspofungin
Nucleic acid synthesis: 5-fluorocytosine
Ergosterol synthesis: fluconazole…-azole

Question 10

Membrane function: Amphotericin B

Answer 10

Large polyene macrolides derived from streptomyces
Mechanism: binds ergosterol in fungal cell membranes-inserts into membrane to form pores
Hydrophilic core creates pores which allow movement of ions and small molecules
Disturbs ionic balances-loss K+
Patch clamp

Fungus

Question 11

DNA synthesis: Flucytosine

Answer 11

Mechanism: take up by cytosine permease, converted to 5-fluorouracil(5-FU) by cytosine deaminase(HUMANS DON’T HAVE THIS ENZYME)

5-FU converted to 5-UMP and then 5-UTP and incorporated into aRNA or converted by ribonucleotide reductase to 5-FdUMP-Potent inhibitor of thymidylate synthase

Question 12

Ergosterol synthesis: Azoles

Answer 12

Mechanism: inhibit fungal CYP enzymes that are essential for ergosterol production
Leads to alteration in membrane fluidity so alters activity of membrane associated enzymes
Mammalian CYP affected as well-extensive drug inteations

Two classes***
Imidazoles(has C): less selective
Triazoles(has N): more selective

Question 13

Cell wall synthesis: Echinocandins

Answer 13

Ex. caspofungin
Mechanism: inhibit activity of glucan synthase complex-result in loss of structural integrity of cell wall-less beta-1,3-glucan is synthesized

Question 14

Protozoa

Answer 14

Unicellular organism that share many characteristics to human, MALARIA=fever, shivering, convulsions and coma=resistant to pesticides and anti-protozoal drugs

Question 15

Malaria

Answer 15

Spread by mosquito host and 4 species:
P. falciparum – Predominant in Africa, most dangerous,
blood clots, no exo-erythrocytic stage
P. vivax – Not found in Africa, can live in liver for years, predominant in Asia
P. ovale – Mainly Africa, rare
P. malariae - No exo-erythrocytic stage

Question 16

Chloroquine

Answer 16

Mechanism: major action of chloroquine is to inhibit the formation of hemozoin(Hz) from the heme released by the digestion of hemoglobin(Hb)
Free heme lyses membrane=parasite death
Resistance: decreased accumulation of chloroquine in food vacuole
Anti-viral effect seen in vitro

Question 17

Remdesivir

Answer 17

Broad spectrum antiviral agent shown to decrease COVID
Discovered for ebola
Anti-viral covid effect seen in mice
Mechanism: Target RNA dependent polymerase, delete chain termination:disrupt RNA synthesis