Bacterial Structure, Function and Growth III - Targets for antimicrobial therapy (If we need to go into this much detail??)

Question 1

Cell wall-active antimicrobials

Answer 1

Selective toxicity is due to the lack of peptidoglycan in mammalian cells.

a. β-lactams (penicillins, cepalosporins, etc) inhibit the final transpeptidation reaction in cross-linking of peptidoglycan.
b. Vancomycin inhibits utilization of lipid-linked intermediate at an intermediate step in peptidoglycan synsthesis, e.g., elongation of the peptidoglycan chain.
c. Cycloserine inhibits alanine racemase, preventing

Question 2

Outer and cytoplasmic membrane-active antimicrobials:

Answer 2

Polymyxins are cationic surfactants that disrupt bacterial outer and cytoplasmic membranes. They are less active on mammalian cell membranes

Question 3

Inhibitors of protein synthesis at the ribosomal level.

Answer 3

Selective toxicity is due to differences between bacterial and mammalian ribosomes.

a. Aminoglycosides (including streptomycin, kanamycin, gentamicin, neomycin, tobramycin, amikacin, etc) bind to specific target proteins in the 30S ribosomal subunit and inhibit protein synthesis.
b. Tetracyclines reversibly bind to the 30S ribosomal subunit and inhibit binding of aminoacyl tRNA.
c. Chloramphenicol binds reversibly to the 50S ribosomal subunit and inhibits peptidyl transferase and peptide bond formation.
d. Macrolides (such as erythromycin) and lincomycins (such as lincomycin and clindamycin

Question 4

Inhibitors of nucleic acid synthesis.

Answer 4

a. Quinolones inhibit DNA gyrase and topoisomerase and therefore interfere with DNA replication.
b. Rifampicin inhibits RNA polymerase and interferes with the initiation of transcription.

Question 5

Metabolic inhibitory antimicrobials.

Answer 5

a. Sulfonamides are structural analogs of p-aminobenzoic acid (PABA), which is a component of folic acid. Enzymes that use folic acid derivatives as coenzymes are needed for one-carbon transfer reactions in the synthesis of many compounds, including thymidine and purines. Sulfonamides inhibit the formation of folic acid by competing with PABA, and this in turn prevents nucleic acid synthesis. The inhibition is selective because only bacteria, and not the host, possess enzymes for making folic acid (we get ours from the bacteria), whereas bacteria, in contrast to human cells, cannot utilize pre-formed folic acid.
b. Trimethoprim also interferes with folate metabolism by inhibiting the enzyme dihydrofolate reductase. Since both bacterial and host cells both possess this enzyme, the basis of selective toxicity lies in the 50,000-fold greater sensitivity of the bacterial enzyme to this drug.
c. Isoniazid inhibits lipid synthesis (probably mycolic acid synthesis) in susceptible Mycobacteria.
d. Metronidazole appears to specifically interfere with anaerobic metabolism.