Name all the ways drugs achieve selective toxicity against bacteria
1. Disrupt DNA & Cell Division
2. Disrupt Protein Synthesis
3. Damage Bacteria's Plasma Membrane
4. Damage Bacteria's Cell Wall
5. Concentrate in Target Cells
6. Be a Pro-drug that's Activated Only in Target Cells
7. Administer Systemically Toxic Drug Only Locally
What are the ways that drugs can disrupt DNA & Cell division?
1. Interfere with topoisomerase II gyrase & topoisomerase IV supercoiling to prevent coiling of DNA: Fluoroquinolones, Nitroimidazoles.
2. Inhibit DNA-dependent RNA polymerase: Rifampin
3. Inhibit viral DNA polymerase: Acyclovir (NB anti-virus, not antibacterial)
4. Interact with DNA to cause chain breakage: Nitroimidazoles.
5. Prevent cell division by interfering with microtubule structure, thus mitosis, preventing cell growth: Griseofulvin (anti-fungal) & Benzimidazole
6. Disrupt DNA synthesis with nucleic acid analogue (base analogue): 5-Flucytosine aka Ancobon, used against yeast
Fluoroquinolones, Nitroimidazoles, Griseofulvin & 5-Flucytosine are more important.
What are ways drugs can disrupt protein synthesis?
1. Initiation of translation: Block tRNA binding to amino-acyl site on ribosome by binding to 30S subunit of ribosome - Tetracyclines.
2. Peptidyl-transferase step: Inhibit peptidyl-transferase step in protein synthesis, binding to 50S subunit of ribosome - Chloramphenicol.
3. Misreading of mRNA, leading to nonsense/truncated proteins - Aminoglycosides
4. Prevent peptide translocation on ribosome - Fusidic acid
5. Bump off peptide chain from ribosome during translocation - Macrolides
6. Prevent peptide elongation on the ribosome - Lincosamides
7. Cause distortion of amino-acyl/tRNA binding site & block production of peptide - Streptogramins
Name some antimicrobial drugs or drug groups that work by inhibiting or disrupting DNA synthesis and repair.
1. Fluoroquinolones & Nitroimidazoles - supercoiling, gyrase, transcription
2. Griseofulvin & Benzimidazole - prevent cell division by interfering with microtubule structure & mitosis
3. 5-flucytosine - analogue of DNA base Pyrimidine
Name the seven antimicrobial drug groups that work by disrupting protein synthesis. Think PROTEIN = CAT DIETS
Tired Cats Ate Fresh Meat Like Steak
4. Fusidic acid
Name antimicrobials that work by damaging or disrupting the synthesis of bacteria or fungi's cell membranes.
1. Polymyxins - destabilise membrane
2. Ionophores - form ion pores in membrane
3. Azoles - inhibit synthesis of ergosterol (anti-fungal)
4. Nystatin - binds to ergosterol, disrupting membrane (anti-fungal)
Which antimicrobials work by damaging the bacteria's cell wall ie., targeting peptidoglycans (remember fungi/yeast don't have cell walls). Name in chronological order of cell-wall formation.
1. Cycloserine: Inhibits initial peptidoglycan-formation step of D-ala chain
2. Bacitracin: Inhibits transport of early peptidoglycan subunits across membrane
3. Glycopeptides: Inhibit transport of later peptidoglycan chain across cell membrane
4. Beta-lactams (Penicillins & Cephalosporins) - Inhibit final step of X-linking of peptidoglycans polymer D-Ala-D-Ala
Which antimicrobials work by concentrating in a target tissue?
Tetracyclines- concentrate strongly in bacteria vs. host cells, ie., good against intracellular pathogens. Tetracyclines disrupt protein synthesis by blocking tRNA binding to amino-acyl site on ribosome. They binds to the 30S subunit of the ribosome.
What are pro-drugs that are activated only when it's in its target cells?
2. Flucytosine converts to 5-fluoracil in fungal cells
3. Acyclovir is activated by viral kinases
What are some Fluoroquinolones?
Naladixic acid (quinolone)
How do Fluoroquinolones work?
Nucleic-acid (DNA) synthesis inhibitors: Interfere with topoisomerase II gyrase & topoisomerase IV supercoiling to prevent supercoiling of DNA necessary for transcription.
Are Fluoroquinolones lipophilic? How is fluoroquinolone excreted? What are the side effects?
Highly lipophilic with ability to concentrate heavily in bacterial cells vs host cells. Despite being lipophilic, they are excreted unchanged in urine & bile. Side effects: Damage cartilage in growing animals esp puppies.
What are Fluoroquinolones used to treat?
Gram (+) cocci eg. Staphylococcus
“Difficult” Gram (-) Obligate anaerobes
Poor against infections involving Streptococci or enterococci
Name two antimicrobial drug groups that work by preventing bacteria from synthesizing folate, which they need for carbon metabolism.
1. Sulphonamides: PABA analogue / competitive inhibitor that prevents enzyme catalysis of PABA → folate
2. Trimethoprim - Prevents action of dihydrofolate reductase (DHR) to reduce FH2 to FH4 tetrahydrofolic acid for use as nuclei-acid building block.
Sulphonamide & Trimethoprim are best used together to interfere with both enzymes that catalyse usable folate.
Which antimicrobial drugs are highly hydrophilic, not metabolised by liver & thus pass unchanged in urine?
1. All the beta-lactams: Penicillin, Cephalosporin, Carbapenem.
2. Aminoglycosides (Gentamicin, Neomycin, Streptomycin, Tobramicin)
Which antimicrobial drugs are lipophilic and metabolised by liver but to varying degrees only and are thus excreted in urine &/or faeces?
3. Potentiated sulphonamides
4. Fluoroquinolones - even though highly lipophilic
Explain the differences between beta-lactams in terms of resistance and sensitivity to beta-lactamase.
Beta-lactamase is an enzyme secreted by Staphylococci & Gram (-) bacilli such as E. coli. Some beta-lactams are sensitive to it & thus should not be used to fight Staph, while others are resistant & are effective in fighting Staph.
Beta-lactamase sensitive: Amoxycillin, Penicillin G NB NEVER give Penicillin G to guinea pig or it will die.
Beta-lactamase resistant: Cloxacillin, Cephalosporin, Amoxycillin + Clavulanic acid combo (*** Clavulanic aid INHIBITS beta-lactamase! & allows Amoxy to work)
Why would you choose Amoxycillin + Clavulanic acid to treat a kidney infection in a cat?
A kidney infection could be could be caused by Escherichia coli, a Gram (-) bacillus bacteria that can cause UTI. Beta-lactams such as penicillins & cephalosporins have wide spectrum activity to treat both Gram (+) & (-) bacteria. Also, since penicillins are very hydrophilic, they are filtered in the kidney unchanged, so they are still biologically active when they reach the urinary tract. Fluoroquinolones are also effective, with wide spectrum activity, against Gram (-) bacilli bacteria, and is filtered unchanged by the kidney even though it's lipophilic, but E. coli has shown some resistance to it with efflux pumps.
Since E. coli secretes ß-lactamase, a ß-lactamase-resistant penicillin must be used. However, in order to avoid resistance, you could use Amoxycillin (broad spectrum), which is susceptible to ß-lactamase, along with clavulanic acid, which inhibits production of ß-lactamase but has no other antimicrobial qualities.
Why are drugs that target bacterial cells' cytoplasmic membranes have less selective toxicity than those that target the cell wall?
All bacteria have cytoplasmic membranes so it's non-selective to target them, while not all bacteria have cell walls of the same thickness (Gram-neg have thin walls, Gram-pos have thick walls).
To which antimicrobial group do the following antibiotics belong? Gentamicin Streptomycin Neomycin Tobramicin
Aminoglycosides. These disrupt protein synthesis (the hint is in "amino") by causing a mis-reading of the mRNA, leading to a nonsense code and/or truncated protein in translation. Aminoglycosides are cidal & filtered in kidney, excreted in urine. Effective against Gram (-) bacilli such as Pseudomonas aeruginosa, which is resistant to many other types of antibiotics.
Which antimicrobials undergo enterohepatic recirculation, and why is this important in their use?
Macrolides & Lincosamides undergo enterohepatic recirculation aka enterohepatic recycling: Recirculation of drugs from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. This causes an increased drug effect, like another dose. Macrolides & Lincosamides are lipophilic, so they are metabolised by the liver & excreted in faeces. Macrolides & Lincosamides interfere with protein synthesis: Macrolides are big and bump off peptides from ribosomes during translocation while Lincosamides prevent elongation of the peptide chain.
What are the names of some Macrolides?
Erythromycin Tylosin (pigs, dogs) Tulathromycin Azithromycin (human)
What are some names of Lincosamides?
Why are Macrolides effective against Gram (+) bacteria but not Gram (-)?
Macrolides are really big so they can't make it through the outer cell membrane. An exception is Azythromycin, used in human Gram (-) bacilli bacteria infections, which can enter the outer membrane. Macrolides are used more against Gram (+) cocci like Streptococci uberis, which causes mastitis, if beta-lactams don't work.
What antimicrobial drugs can be used to treat ringworm (Microsporum canis, a dermatophyte)?
1. Griseofulvin - Interferes with microtubule structure, thus mitosis, preventing fungal-cell growth. However, it is teratogenic. 2. Azole (eg. Ketoconaozole) - Inhibits synthesis of ergosterol & thus fungal-cell membrane. Also teratogenic.
Name 10 families of antimicrobial drugs.
1. Penicillins 2. Cephalosporins 3. Aminoglycosides 4. Macrolides & Lincosamides 5. Glycopeptides 6. Fluoroquinolones 7. Tetracyclines 8. Nitroimidazoles 9. Chlorampenicols 10. Sulphonamides & Potentiated Sulphonamides
Of the 10 families of antimicrobial drugs, which are cidal (kill bacteria)?
Five families are bacteriocidal: The beta-lactams are cidal: - Penicillin - Cephalosporins - Fluoroquinolones - Nitroimidazole - Aminoglycosides
Of the 10 families of antimicrobials drugs, which are static (inhibit growth)?
Five families are bacteriostatic: Most of those that inhibit protein synthesis are static except for Aminoglycosides: - Tetracyclines - Chloramphenicol - Macrolides & Lincosamides - Glycopeptides - Sulphonamides & Potentiated Sulphonamides
Which families of antimicrobial drugs ONLY have narrow-spectrum of activity?
Most drugs that inhibit protein synthesis have narrow spectrum except Tetracyclines & Chloramphenicol: - Aminoglycosides - Macrolides & Lincosamides and - Nitroimidazoles
Which families of antimicrobial drugs ONLY have broad spectrum activity?
- Tetracycline - Chloramphenicol - Cephalosporins - Sulphonamides & Potentiated Sulphonamides