Medicinal chemistry of antimycobacterial agents - 4 questions

Question 1

• State the name of the organism that causes tuberculosis

Answer 1

• Mycobacterium tuberculosis

Question 2

• Discuss what is meant by “acid fast bacteria.” Be able to explain how this can be used to diagnose active tuberculosis infections

Answer 2

• Bacteria that have a unique cell wall that is high in lipids which makes them resistant to decolorization by acid during staining procedures. They almost are a red-ish orange color

Question 3

• Describe the composition of the mycobacterial cell wall, how it differs from the cell walls of Gram-negative and Gram-positive bacteria, and how it influences mycobacterial susceptibility to antibiotics

Answer 3

• Has arabinogalactan and mycolic acid rich layers. These layers are not present in gram positive or gram-negative bacteria. These layers add significant barriers to penetration for many antibiotics particularly the ones that are hydrophilic

Question 4

• *** Describe the activation, mechanism of action, the mechanism by which bacteria can become resistant, and the contribution each drug makes to an effective antituberculosis treatment for each of the following:
• Isoniazid

Answer 4

• Pro-drug activated by M. tb KatG protein
• Only active against growing cells
• Forms adducts with NAD+ and NADP+ and by doing this it inhibits enzymes that’s use NAD+ and NADP+
• Inhibits InhA (component of FAS II)
• Resistance in 2 ways: 1. Over expression of inhA (lower levels of resistance), 2. Activation by KatG is inhibited (higher rate of resistance)

Question 5

• *** Describe the activation, mechanism of action, the mechanism by which bacteria can become resistant, and the contribution each drug makes to an effective antituberculosis treatment for each of the following:
• Rifampin

Answer 5

• Semisynthetic derivative of rifamycin B
• Active against growing and stationary cells
• MOA: Bactericidal, binds to RNA polymerase deep withing the DNA/RNA channel

Question 6

• *** Describe the activation, mechanism of action, the mechanism by which bacteria can become resistant, and the contribution each drug makes to an effective antituberculosis treatment for each of the following:
• Ethambutol

Answer 6

• Bacteriostatic inhibitor of M. TB
• MOA: Inhibits mycobacterial arabinosyl transferases leading to inhibition of arabinogalactan and lipoarabinomannam
• Resistance: Due to over-expression of or mutation in arabinosyl transferase

Question 7

• *** Describe the activation, mechanism of action, the mechanism by which bacteria can become resistant, and the contribution each drug makes to an effective antituberculosis treatment for each of the following:
• Pyrazinamide

Answer 7

• Pro-drug: requires conversion to pyrazinoic acid by pncA
• Activity is pH dependent
• MOA: not fully known but likely inhibition of fatty acid synthase type I leading to interference with mycolic acid synthase, also shown to inhibit PanD which is involved in making CoenzymeA
• Resistance: Mutation in PanD that leads to Pyrazinoic acid not being able to bind, Mutation in pncA

Question 8

• *** Describe the activation, mechanism of action, the mechanism by which bacteria can become resistant, and the contribution each drug makes to an effective antituberculosis treatment for each of the following:
• Moxifloxacin

Answer 8

• MOA: Bactericidal, Traps Gyrase on DNA as ternary complex and prevents resolution of supercoiled DNA
• Resistance: Change in cell wall permeability, Mutation in DNA repair, alteration of enzyme, efflux pumps

Question 9

• *** Describe the activation, mechanism of action, the mechanism by which bacteria can become resistant, and the contribution each drug makes to an effective antituberculosis treatment for each of the following:
• Bedaquiline

Answer 9

• MOA: Inhibit ATP synthase, bactericidal against growing and dormant cells
• Resistance: Mutation in atpE

Question 10

• *** Describe the activation, mechanism of action, the mechanism by which bacteria can become resistant, and the contribution each drug makes to an effective antituberculosis treatment for each of the following:
• Pretomanid

Answer 10

• Pro-drug: activated by M. Tb deazaflavin-dependent nitroreductase
• MOA: in aerobic conditions: forms reactive intermediate metabolite that inhibits mycolic acid production. In anaerobic, nonreplicating, persistent bacilli: generates reactive nitrogen species such as NO which leads to direct poisoning and depletion of ATP

Question 11

• List and discuss the reasons that a drug may be classified as a second line agent to treat tuberculosis. Be able to provide examples of second line agents.

Answer 11

• Streptomycin, ethionamide, cycloserine, capreomycin
• Second line usually because they are less tolerated