Antibiotics: DNA/RNA Biogenesis Inhibitors

Question 1

Why folate is required for DNA synthesis:

Answer 1

Converts dUMP to dTMP

Involved in formation of purine aromatic ring

Question 2

Sulfonamides (sulfamethoxazole) mechanism of action:

Answer 2

Competitive inhibitor of dihydropteorate synthase. Analog of PABA (para-aminobenzoic acid).

Question 3

Trimethoprim mechanism of action:

Answer 3

Competitive inhibitor of DHFR. 50,000x more efficacious against bacterial DHFR than mammalian DHFR.

Question 4

SMX/TMP pharmacodynamics and spectrum:

Answer 4

Generally bacteriostatic. NEVER USE IN LIFE-THREATENING INFECTIONS. Effective against some GPC (S. pneumoniae), some GNR (E. coli, H. flu, Moxarella), and PNEUMOCYSTIS JIROVECII.

Question 5

SMX/TMP clinical use:

Answer 5

Respiratory tract infections, otitis, UTIs, prostatitis, MRSA skin and soft tissue.

Question 6

SMX/TMP toxicity:

Answer 6

Allergy (erythema multiforme and skin rashes), bone marrow suppression, GI upset, hepatitis, hyperkalemia. Avoid in first trimester of pregnancy.

Question 7

TMP resistance:

Answer 7

Reduced DHFR binding affinity.
Overexpression of the enzyme.
Reduced bacterial permeability.

Question 8

Fluoroquinolones mechanism of action:

Answer 8

Irreversibly binds to DNA/enzyme (gyrase) complexes, intercalating in DNA. Replication cannot proceed through these complexes.

Question 9

Fluoroquinolones resistance:

Answer 9

Reduced enzyme binding due to mutations. Impaired permeability and increased drug efflux. Protection of DNA gyrase by QNR proteins.

Question 10

Ciprofloxacin spectrum:

Answer 10

Bacteriocidal. Poor against GPC, good against GNRs (Pseudomonas, E. coli), Legionella, and Mycobacterium avium intracellulare.

Question 11

Moxifloxacin/levofloxacin spectrum:

Answer 11

Wide spectrum. GPCs, GNRs, and chlamydia.

Question 12

Fluoroquinolone pharmacokinetics:

Answer 12

Concentration-dependent killing.
Ciprofloxacin - t1/2 = 3-5 hours, hepatic and renal clearance.
Moxifloxacin/levofloxacin - t1/2 = 24 hours, minimal concentration in urine.

Question 13

Fluoroquinolone clinical uses:

Answer 13

Ciprofloxacin: UTIs, STDs
Moxifloxacin: Pneumonia
Levofloxacin: Pneumonia, UTIs

Question 14

Fluoroquinolone toxicity:

Answer 14

GI upset, rashes, seizures, ciprofloxacin inhibits P450. Rarely: bone marrow failure, hemolytic anemia, nephrotoxicity.

Question 15

Metronidazole mechanism of action:

Answer 15

Reduced by nitroreductase (found in anaerobes). Forms single-strand breaks, mainly at A-T base pairs. Radicals may also damage lipids and proteins.

Question 16

Metronidazole spectrum:

Answer 16

Bacteriocidal. Used for oral and bowel anaerobes, C. difficile, protozoa (Giardia and Entamoeba).

Question 17

Metronidazole pharmacokinetics:

Answer 17

CDK with significant post-antibiotic effect (PAE). Hepatic metabolism, which inhibits CYP3A and aldehyde dehydrogenase (which produces disulfiram-like effect).

Question 18

Metronidazole toxicity:

Answer 18

GI upset, metallic taste in mouth, CNS effects (ataxia, vertigo), neutropenia, dark urine, TERATOGENIC.

Question 19

Rifamycin (rifampin) mechanism of action:

Answer 19

Binds to the beta subunit of bacterial RNA polymerase, inhibiting further RNA production. Affects mitochondrial RNA polymerase at extremely high doses.

Question 20

Rifampin spectrum:

Answer 20

Most GPCs, many GNRs. Also effective against Legionella, N. meningitidis PROPHYLAXIS, and intracellulars.
Bacteriostatic against MYCOBACTERIUM. Bacteriocidal against S. AUREUS.

Question 21

Rifampin resistance:

Answer 21

Mutations in beta-subunit binding site of RNA polymerase. Never use alone for TB therapy.

Question 22

Rifampin toxicity:

Answer 22

GI upset, hepatitis, jaundice, ORANGE DISCOLORATION OF TEARS, URINE, headaches, drowsiness, thrombocytopenia, drug fever (serum sickness, flu-like symptoms), CYP450 INDUCER!