Inhibitors of Nucleic Acid Synthesis
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What is the function of the enzyme helicase during DNA synthesis?

  • Joins together the Okazaki fragments of the lagging strand
  • Synthesizes a short strand of RNA called primer
  • Unzips the double strand structure of the DNA (correct)
  • Matches and adds new nucleotides to form daughter DNA strand

    • Which of the following is NOT an inhibitory effect of quinolones?

  • DNA strand breakage by a direct chemical action
  • Unzipping of DNA (correct)
  • Blocking of DNA replication fork
  • Inhibition of DNA synthesis

    • What is the function of the enzyme primase during DNA synthesis?

  • Joins together the Okazaki fragments of the lagging strand
  • Matches and adds new nucleotides to form daughter DNA strand
  • Unzips the double strand structure of the DNA
  • Synthesizes a short strand of RNA called primer (correct)

    • What is the spectrum of activity of metronidazole?

    <p>Active only against anaerobic organisms</p> Signup and view all the answers

    What is the mechanism of action of nitroimidazoles and nitrofurans?

    <p>DNA strand breakage by a direct chemical action</p> Signup and view all the answers

    Which enzyme is responsible for joining together the Okazaki fragments of the lagging strand?

    <p>DNA ligase</p> Signup and view all the answers

    What is the function of the enzyme topoisomerase during DNA synthesis?

    <p>Relieves the stress generated by unzipping of DNA</p> Signup and view all the answers

    What is the mechanism of action of trimethoprim when used alone?

    <p>Bacteriostatic inhibition of growth</p> Signup and view all the answers

    What is the function of the enzyme exonuclease during DNA synthesis?

    <p>Removes the short segments of primers and is replaced by DNA polymerase</p> Signup and view all the answers

    What is the main difference between fungal and bacterial cell walls?

    <p>Fungal cell walls are composed of chitin</p> Signup and view all the answers

    Which of the following is an example of an anaerobic Gram-negative bacillus that is sensitive to metronidazole?

    <p>Bacteroides fragilis</p> Signup and view all the answers

    What is the name of the fungal enzyme inhibited by allylamine?

    <p>Squalene epoxidase</p> Signup and view all the answers

    What is the mechanism by which metronidazole is activated within cells?

    <p>By low redox potentials within the cells</p> Signup and view all the answers

    What is the brand name of terbinafine?

    <p>Lamisil</p> Signup and view all the answers

    What is the mode of reproduction of yeast?

    <p>Budding</p> Signup and view all the answers

    What is the type of fungus that grows partly as yeast and partly as filaments called hyphae?

    <p>Yeast-like fungi</p> Signup and view all the answers

    What is the effect of combining trimethoprim with sulfamethoxazole?

    <p>Synergistic effect</p> Signup and view all the answers

    What is the mechanism of action of nystatin?

    <p>Inhibition of fungal membrane function and integrity</p> Signup and view all the answers

    What is the type of fungal infection caused by Histoplasma capsulatum?

    <p>Histoplasmosis</p> Signup and view all the answers

    What is the type of fungus that reproduces by forming spores?

    <p>Mould</p> Signup and view all the answers

    What is the primary target of rifampicin in bacterial cells?

    <p>RNA polymerase</p> Signup and view all the answers

    Which of the followingprotozoa is not susceptible to rifamycins?

    <p>Trichomonas vaginalis</p> Signup and view all the answers

    What is the role of tetrahydrofolate in cells?

    <p>Carrier of single carbon fragments</p> Signup and view all the answers

    Why do sulphonamides and sulphones inhibit bacterial growth?

    <p>By inhibiting the incorporation of PABA into dihydropteroic acid</p> Signup and view all the answers

    What is the difference between bacterial and mammalian cells in terms of folate utilization?

    <p>Mammalian cells can take up exogenous folate, while bacteria cannot</p> Signup and view all the answers

    What is the mechanism of action of trimethoprim?

    <p>Inhibiting dihydrofolate reductase</p> Signup and view all the answers

    Which of the following antimicrobial agents is not an inhibitor of metabolic pathways?

    <p>Rifampicin</p> Signup and view all the answers

    What is the primary use of rifampicin in clinical practice?

    <p>Treatment of mycobacterial infections, such as tuberculosis</p> Signup and view all the answers

    Which of the following is not an anaerobic Gram-positive bacillus?

    <p>Bacillus subtilis</p> Signup and view all the answers

    What is the difference between sulphonamides and sulphones in terms of their mechanism of action?

    <p>There is no difference in their mechanism of action</p> Signup and view all the answers

    What is a rare side effect associated with oral treatment of terbinafine?

    <p>Hepatotoxicity</p> Signup and view all the answers

    What is the mechanism of action of echinocandins?

    <p>Blocks the synthesis of β(1→3) glucan found in fungal cell walls</p> Signup and view all the answers

    What is the nickname of echinocandins?

    <p>Penicillin for fungi</p> Signup and view all the answers

    What is the organism from which caspofungin is derived?

    <p>Glarea lozoyensis</p> Signup and view all the answers

    What is the primary action of undecylenic acid?

    <p>Fungistatic</p> Signup and view all the answers

    What is the combination of agents in Whitfield's ointment?

    <p>Benzoic acid and salicylic acid</p> Signup and view all the answers

    What is the indication for the use of Whitfield's ointment?

    <p>Tinea pedis</p> Signup and view all the answers

    Which of the following fungi is not susceptible to tolnaftate?

    <p>Candida albicans</p> Signup and view all the answers

    What is the mechanism of action of echinocandins similar to?

    <p>Penicillin</p> Signup and view all the answers

    What is the antifungal compound that is primarily fungistatic but may exhibit fungicidal activity at high concentrations?

    <p>Undecylenic acid</p> Signup and view all the answers

    Study Notes

    Nucleic Acid Synthesis Inhibitors

    • Nucleic acids, including DNA and RNA, are biopolymers made up of monomers called nucleotides.
    • Enzymes involved in nucleic acid synthesis are attractive therapeutic targets for various diseases.

    Elongation

    • Primase binds to the first priming sequence on the leading strand template and synthesizes a short RNA primer that is complementary to the DNA template.
    • DNA polymerase uses the primer to initiate DNA synthesis by adding deoxyribonucleotides to the 3’ end.

    Enzymes Involved in Nucleic Acid Synthesis

    • Helicase: unzips the double-strand structure of DNA.
    • DNA polymerase: matches and adds new nucleotides to form daughter DNA strands.
    • Primase: synthesizes a short strand of RNA called a primer.
    • DNA ligase: joins together the Okazaki fragments of the lagging strand.
    • Topoisomerase: relieves the stress generated by unzipping of DNA.
    • Exonuclease: removes short segments of primers and is replaced by DNA polymerase.

    Quinolones

    • Nitroimidazoles and Nitrofurans (e.g., Metronidazole and Nitrofurantoin): cause DNA strand breakage by direct chemical action.
    • The nitro group of Metronidazole is converted to nitronate radical by low redox potentials within the cells.
    • The activated Metronidazole then attacks the DNA, producing strand breakage.

    Spectrum of Activity of Metronidazole

    • Active only against anaerobic organisms.
    • Anaerobic Gram-negative bacilli: Bacteroides fragilis, Bacteroides species, Fusobacterium spp., Porphyromonas spp., Prevotella spp.
    • Anaerobic Gram-positive bacilli: Clostridium spp.
    • Anaerobic gram-positive cocci: Peptostreptococcus species, Veillonella species.
    • Also an antiprotozoan: effective against Blastocystis hominis, Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis.

    Rifamycins

    • Rifampicin is a semisynthetic member of the rifamycin family and functions by blocking RNA polymerase activity in bacteria.
    • The RNA polymerase enzymes in bacteria are structurally different from those in eukaryotes, providing for selective toxicity against bacterial cells.
    • Used for the treatment of various infections, including tuberculosis.

    Inhibitors of Metabolic Pathways

    Folate Metabolism

    • Folic acid is an essential co-factor in all living cells.
    • In its reduced form (Tetrahydrofolate THF), folic acid functions as a carrier of single carbon fragments used in the synthesis of adenine, guanine, thymine, and methionine.
    • Bacteria, protozoa, and mammalian cells possess Dihydrofolate receptor (DHFR), but there are sufficient differences in the enzyme structure for inhibitors like trimethoprim to inhibit bacterial enzymes selectively.

    Sulphonamides and Sulfones

    • Structural analogues of PABA.
    • Competitively inhibit the incorporation of PABA into dihydropteroic acid, inhibiting subsequent metabolism.
    • Bacteriostatic inhibition of growth against a broad spectrum of gram-positive and gram-negative pathogens.

    Trimethoprim

    • Synthetic antimicrobial compound that serves as an antimetabolite in the same folic acid synthesis pathway as sulphonamides.
    • Selective inhibitor of bacterial dihydrofolate reductase.
    • Used in combination with sulfa drugs, such as sulfamethoxazole, to treat urinary tract infections, ear infections, and bronchitis.

    Antifungal Agents

    • Fungi are eukaryotic organisms that live as saprobes or parasites.
    • Fungal cell membrane contains ergosterol, whereas human cell membrane contains cholesterol.
    • Antibacterial agents are not effective against fungi.
    • Fungal infections are also called mycoses.

    Types of Fungi

    • Yeasts: reproduce by budding (e.g., Cryptococcus neoformans, which causes cryptococcal meningitis).
    • Yeast-like fungi: grow partly as yeast and partly as filaments called hyphae (e.g., Candida albicans, which causes oral, vaginal, and systemic candidiasis).
    • Dimorphic fungi: grow as mould or as yeast (e.g., Histoplasma capsulatum, which causes histoplasmosis).
    • Moulds: filamentous fungi that reproduce by forming spores (e.g., Dermatophytes, which cause hair, skin, and nail infections such as ringworm).

    Nystatin

    • Isolated from Streptomyces noursei.
    • Polyene macrolide similar to amphotericin B in structure and action.
    • Used for superficial candidiasis of the mouth, skin, vagina, and intestine.
    • More toxic than Amphotericin B when used parenterally.

    Allylamine

    • E.g., Terbinafine, Butenafine, Naftifine.
    • Inhibit the fungal enzyme Squalene epoxidase, which converts squalene to lanosterol.
    • Leads to a reduction in lanosterol production, affecting cell membrane function and integrity.
    • Fungicidal.
    • Terbinafine is used topically for the treatment of dermatophytic skin infections like athlete’s foot, ringworm, and jock itch.

    Echinocandins

    • The echinocandins, including caspofungin, are naturally produced antifungal compounds.
    • Caspofungin is derived from the fermentation product of Glarea lozoyensis.
    • Blocks the synthesis of β(1→3) glucan found in fungal cell walls but not in human cells.
    • Used for the treatment of aspergillosis as well as systemic yeast infections.

    Other Topical Agents

    • Tolnaftate: effective against most cutaneous mycoses caused by Trichophyton rubrum, T. tonsurans, M. gypseum, and M. canis, but ineffective against Candida.
    • Undecylenic acid: used in the treatment of various dermatomycoses, especially tinea pedis; primarily fungistatic but may exhibit fungicidal activity with long exposure to high concentrations.
    • Benzoic acid and salicylic acid: components of Whitfield's ointment, which combines the fungistatic action of benzoate with the keratolytic action of salicylate; used for the treatment of tinea pedis.

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