Mycobacterial Agents Med Chem Flashcards
1
Q
TB Drug Regimens
A
-8 week - intensive phase using four drugs
FOLLOWED BY
-18 week - continuation phase using 2 drugs
-Multi-drug regimens help reduce resistance
-Drugs target TB’s different physiological states/sites
2
Q
Extensive TB looks like….
A
- Lesions are heterogenous
- Some are caseous and some are cavitating
3
Q
TB Granuloma Structure
A
- Outer granuloma: increased O2 and pH (neutral), active bacilli
- Necrotic core: Decreased O2 and pH (acidic), dormant bacilli
- O2 cannot diffuse into the core (glycolysis)
4
Q
Rifampicin
A
- 6 H-bond donors and 15 H-bond acceptors
- Absorption decreased by concurrent administration with antacids
- Due to hydroxyl’s strong bond to the metal, N+
- Decreases solubility in the GI (ionizable amine)
5
Q
Rifampicin Properties
A
- Half-life ~4 hours
- Inhibits DNA dependent RNA polymerase
- Potently bactericidal
- Resistance: point mutations in rpoB decreased binding and inhibition, compensatroy mutations in rpoA and rpoC (high level resistance)
- Strong inducer of -450s, especially CYP3A4
6
Q
Why is rifampicin so good?
A
- Kills all kind of TB physiology (active dormant, intra/extracellular, oxic/hypoxic)
- Accumulates with multiple doses in necrotic cores of granulomas where most difficultly treated bacteria is contained
- Granuloma levels are above MAC and MIC
7
Q
Rifabutin
A
- Loses the quinolone and loses most of P450 induction
- Useful in HIV/TB patients
- More side effects: neutropenia, uveitis arthritis syndrome
8
Q
Isoniazid
A
- Great oral availability, not completely understood MoA
- Prodrug, converted to adduct of NAD by katG (non-human enyzme)
- IN-NAD inhibits inhA, NAD-dependent enzyme needed for mycolic acid synthesis
- INH binds to close, different site to NAD, electron from INH moved to NAD and then released
9
Q
Isoniazid + Necrotic Core Bugs
A
- Good penetration
- Retention in necrotic core, but LESS active in hypoxia
- Doesn’t reach MAC levels, only MIC
- Low kill rate in necrotic core
10
Q
Isoniazid Resistance Mutations
A
- Lose activation by katG: stop codon in katG gene (easy/dominant in vitro), amino acid change at active site (high level resistance, maintains catalase function essential to host)
- Making more target protein (inhA): promotor mutation to enhance inhA expression (low level resistance overcome with high dose INH)
11
Q
Pyrazinamide
A
- Prodrug
- Activated by pncA to POA
- POA has multiple targets, not resolved yet
- Highly dependent on acidic pH => more protonated POA, more killing
- MIC increases significantly with minor increases in acidic pH
12
Q
Pyrazinamide + Necrotic Bugs
A
- ONLY kills necrotic core bugs well
- Good penetration through granuloma BUT only core is acidic
- After two months, cores killed, stop PZA
13
Q
PZA Mutations
A
- Mutations in pncA: mostly point changes leading to amino acid substitutions
- Huge diversity of mutations, only a third of which still have drug susceptibility
14
Q
Ethambutol
A
- Good bioavailability
- Targets cell wall arabinose transferase which is used for cell wall synthesis
- Other targets likely
- LOTS of resistance mutations in different genes
- Clinically effective despite low MIC/MBC => massively accumulates in granuloma compared to others (less in core)
15
Q
HRZE
A
- There is not 4 drug coverage throughout granuloma
- Need at least 2 active drugs to get to site to kill and effectively stop resistance
- Usually rifampin and pyrazinamide mainly
- *Becomes difficult if rifampin resistance develops**
16
Q
Why to stop Z and E?
A
- Dropped going from intensive to continuation phase
- Have significant toxicities so sooner to drop them since no better outcome shown in using them extensively
- 1RHZE kills most bugs/hypoxic acidic anaerobic cores and almost all active cells also killed by 2RHZE (E only bacteriostatic)
17
Q
Why is continuation longer than intensive phase
A
- Actively growing TB buds are more sensitive than non-growing, dormant bugs
- Mix of active/dormant to start but intensive phase wipes out most of the active and leaves mainly dormant (more drug resistant)
- Dormant is weakly sensitive to R but randomly exits dormancy over 4 months where RH combination kills them
18
Q
Latent TB
A
- NOT actively growing TB bugs
- Dormant bacteria where growth is being restrained by host immune system
- Treatment originally 9 months of isoniazid, but 4R was shown to be equally equivalent with less toxicity (not in guidelines yet)
- No way to detect latent MDR
19
Q
MDR/XDR TB
A
- Have to use more toxic and less active drugs over long treatments
- Lots of side effects
- Transmits just as well as normal
- Drug regimens based upon DST susceptibility and side effects, need as many sensitive drugs as possible
- Lesion penetration is less understood, only moxifloxacin known (still excluded from core regions)
20
Q
Ethionamide/Prothionamide
A
- Major activity
- Prodrug
- Converted to adduct of NAD by TB enzyme EthA (monooxygenase)
- Mechanism unknown
- Inhibits inhA, just like INH-NAD adduct
21
Q
Bedaguiline
A
- Inhibits mycobacterial ATP synthesis
- Bactericidal
- Human susceptibility unknown
- Only ionizable group is amine, potentially lower dissolution with acid reduction in stomach
- CYP3A4 metabolized
- 5.5 mo half life
- Potential extended monotherapy if patient drops out of treatment
22
Q
Pretomanid
A
- Prodrug
- Activated by ddn
- Probably to NO, possible other targets
- Easy to develop resistance to since there are 5 non-essential genes in its pathway of activation
23
Q
NTM
A
- Non-tuberculous Mycobacteria
- Generally associated with immunosuppression or local lung problems
- Usually doesn’t have serious effects so debatable on whether to treat
- Regimen: Macrolide/Ethambutol/Rifampin for 12 months after sputum conversion
- 2 years of therapy required for a 20-80% cure rate
- Add injectable aminoglycoside in severe disease (inhaled amikacin is replacing this guideline)
