Medicinal Chemistry of Anti-TB Chemotherapy lecture

Question 1

Mycobacteria

Answer 1

• > 70 species of mycobacteria
• Usually found in wet environments
• Aerobic metabolism, obligate anaerobes
• Unique cell wall structure vital to survival
• Mycobacterial cells are hydrophobic
• N-glycolylmuramic acid in peptidoglycan
• Intracellular pathogens, survive in macrophages
• Cell wall protects cell from oxidative damage

Question 2

Transmission of M. tuberculosis

Answer 2

• Bacteria transmitted by inhalation of droplet aerosol
from person with active pulmonary infection
• Only one organism required to establish infection
• Majority of infections in upper respiratory tract
• Organism implants in the alveoli
• Can reside in phages for many years
• Asymptomatic vs disease

Question 3

Combination Drug Therapy

Answer 3

• Treatment different for new cases vs reinfection
• Limited scope for prophylaxis due to resistance
• Combination therapy, issues around compliance

Question 4

CDT - 1st line

Answer 4

• Isoniazid
• Ethambutol
• Pyrizinamide
• Rifampicin
• (Streptomycin)

Question 5

CDT - 2nd line

Answer 5

• Capreomycin
• Cycloserine
• Fluoroquinolones

Question 6

Isoniazid

Answer 6

• Limited to mycobacteria
• Inhibits synthesis of mycolic acids
• Resistance can occur
• Side effects: hypersensitivity, hepatotoxicity,
CNS disturbances

Question 7

Ethambutol

Answer 7

• Limited to mycobacteria, bacteriostatic
• Inhibits cell wall synthesis
• Resistance emerges rapidly if used alone
• Side effects: dose-related optic neuropathy,
red/green colour blindness, mental disturbances

Question 8

Pyrazinamide

Answer 8

• Tuberculostatic at low pH (~5.5)
• Mechanism of action is unclear but does affect
intracellular organisms in macrophages
• Resistance can occur readily
• Side effects: gout, hepatic damage (high doses)

Question 9

Rifampicin

Answer 9

• Inhibits DNA-dependent RNA polymerase
• Broad spectrum of activity including Gram +ve/-ve
• Enters phagocytes and kills intracellular organisms,
a powerful antituberculosis agent
• Resistance develops rapidly
• Side effects: liver damage, induction of hepatic
metabolising enzymes, influenza-type syndrome

Question 10

Aminoglycoside Mode of Action

Answer 10

• Aminoglycosides are bactericidal
• Bind irreversibly to the 16S rRNA and ‘freeze’ the
30S initiation complex (30S-mRNA-tRNA)
• Binding to 16S rRNA increases the affinity of the
A site for tRNA regardless of anticodon specificity
• Slow down protein synthesis already initiated
• Induce misreading of mRNA
• Gram –ve and some Gram +ve bacteria
• Synergy - effects enhanced by agents that inhibit
peptidoglycan synthesis, e.g. b-lactams
• Ineffective against anaerobic bacteria as oxygen
is required for uptake of the aminoglycosides
• Resistance has developed in many pathogens

Question 11

Aminoglycoside Side Effects

Answer 11

• Serious, dose-related toxic effects
• Ototoxicity – progressive damage to and
destruction of sensory cells in the ear
• Vertigo, loss of balance, deafness
• Nephrotoxicity – damage to kidney tubules
• Combination with cephalosporins increases the
risk of nephrotoxicity
• Rare paralysis due to neuromuscular blockade

Question 12

2nd Line Drugs - Capreomycin

Answer 12

Peptide antibiotic, administered i.m.
• Side effects: kidney damage, damage to eighth nerve
(connects ear to CNS) leading to deafness and ataxia

Question 13

2nd Line Drugs - Cycloserine

Answer 13

• Broad spectrum antibiotic (Gram +ve/-ve)
• Structural analogue of D-Ala, inhibits the
synthesis of peptidoglycan
• Side effects: depression, convulsions, psychosis
• Limited to resistant tubercolosis strains

Question 14

2nd Line Drugs - Fluoroquinolones

Answer 14

• Ciprofloxacin
• Levofloxacin
• Gatifloxacin
• Moxifloxacin

Question 15

Adverse Effects of Quinolone Agents

Answer 15

• Gastrointestinal disturbances
• CNS toxicity
• Dizziness, insomnia, seizures
• Binds to GABAA and NMDA receptors
• Cardiovascular disturbances
• Hepatic disorders, idiosyncratic hepatitis
• Photosensitivity
• Musculoskeletal damage
• Quinolone tendinopathy

Question 16

2nd Generation Macrolides

Answer 16

Clarithromycin
• Increased acid stability, active against Gram +ve

Azithromycin
• Prolonged serum and tissue half-life

Question 17

Macrolides Mode of Action and

Side Effects

Answer 17

• Bacteriostatic or bactericidal (organism dependant)
• Do not affect initiation process
• Inhibit translocation by blocking A site
• Active against a variety of Gram +ve bacteria
• Variable oral activity and stability to acid
• Resistance is widespread, mediated by plasmids
• GI disturbances; secondary infections; jaundice;
hypersensitivity; hearing impairment

Question 18

Linezolid (Zyvox)

Answer 18

• The first oxazolidinone anti-infective to be approved
for clinical use (2002)
• Represented a totally new anti-infective structure with an interesting mode of action
• Active against E. faecium and E. faecalis VRE
• Reports of resistance to linezolid appeared in 2002
• LRVRE reported in 2007

Question 19

Linezolid (Zyvox) SAR

Answer 19

• N-aryl group essential
• Stereochemistry essential
• Acylamino group essential