Fundamentals Block 5: Antibacterial Chemotherapy II: Protein and DNA Synthesis Inhibitors

What are the five Protein Synthesis Inhibitors?

Buy AT 30, CEL (sell) at 50
→ Aminoglycosides, Tetracyclines work at the 30s subunits
→ Clindamycin, Erythromycin (macrolide), and Linezolid work at the 50s subunits

What are Aminoglycoside mechanism of action?

Aminoglycosides exhibit concentration dependent-bactericidal effects due to its irreversible binding
→ Irreversibly inhibit the 30s ribosomal subunit by either blocking initiation of protein synthesis, blocking further translation, or incorporating incorrect amino acids into a sequence

What are the pertinent pharmacokinetics associated with Aminoglycosides

Aminoglycosides are only given via Intravenous or Intramuscular injections
→ Aminoglycosides concentrate highest in the renal cortex and inner ear, contributing to toxicities in these parts (Nephrotoxicity and Ototoxicity)

Describe the concentration-dependent effects of Aminoglycosides

Aminoglycosides exhibit concentration dependent killing - or when their concentration is above the minimum inhibitory concentration
→ as the concentration of the drug rises so does the rate of bacterial killing increase

Aminoglycosides will also exhibit a significant post-antibiotic effect where there is persistent suppression of bacterial growth even when levels drop below the MIC

What is the spectrum of treatment for Aminoglycosides

Aminoglycosides primarily treats Aerobic gram negative bacilli
→ typically pseudomonas

Limited spectrum against gram positive organisms

Aminoglycosides cannot kill anaerobes because it can only penetrate the cytoplasmic membrane in an aerobic energy dependent process

What is the mechanism of action for Tetracyclines?

Tetracyclines
→ inhibit bacterial protein synthesis by reversibly binding to the 30s ribosomal subunit at the site of attachment for tRNA

What are the six kinds of organisms that Tetracycline can treat

Covers both gram positives and gram negatives very well
→ MRSA and other gram positives
→ resistant gram negatives
→ Anaerobes
→ “Atypical” Pneumonia (Mycoplasma, Legionella, and C. pneumoniae)
→ Rickettsiae, Borrelia
→ Some Protozoa

What are the most important side effects associated with tetracyclines? (3)

There are a few pertinent side effects associated with tetracyclines:
→ Skin: Phototoxic reaction - cause you to have a really bad sunburn
→ Can cross the placenta and accumulate in fetal bones, limiting growth (contraindicated in pregnancy)
→ Tooth discoloration in kids

What is Linezolid and what is its mechanism of action

Gram Positive only antibiotic
→ Methicillin Resistant Staph Aureus, streptococci, enterococci, and some mycobacteria
→ distributes well into tissues

Blocks initiation of protein synthesis by interfering with the formation of the initiation complex via binding to the 50s ribosomal subunit

What are the harmful side effects of Linezolid

Leukopenia and serotonin syndrome
→ serotonin syndrome

What is the mechanism of action of Macrolides?

Macrolide
→ reversibly binds to bacterial 23S ribosomal RNA of the 50s ribosomal subunit - inhibits protein synthesis

What are the primary indications for using Macrolides?

Best antibiotic in usage for “atypical” or fastidious pneumonia
→ Mycoplasma, Legionella, C. pneumoniae
→ used quite often in upper and lower respiratory infections, so there is resistance against this very commonly
→ Also used in Bordetella pertussis

What is Clindamycin mechanism of acition?

Inhibits protein synthesis by binding at the 50s ribosomal subunit

When is Clindamycin used

Primarily used to treat gram positive organisms such as MRSA
→ has no activity against aerobic gram negative bacteria

What are the adverse reactions for Clindamycin?

Clindamycin can cause strong Gastrointestinal issues and overgrowth of Clostridium difficile leading to further GI issues

What is the Eagle Effect?

Eagle Effect describes the lack of efficacy of beta-lactam antibiotics on infections with large numbers of bacteria
→ this is because penicillin and related drugs only work when bacteria are actively growing and dividing
→ when an infection is so great, they might all be in stationary phase so no bacteria are really being killed
→ so you would add an antibiotic like clindamycin, which acts on ribosomes, before adding beta-lactams

What is the Fluoroquinolone mechanism of action

Fluoroquinolone
→ binds to DNA gyrase and topoisomerase IV inhibiting DNA synthesis

What is the spectrum of Fluoroquinolones

Antibiotics that are used to treat Gram negative: aerobic gram negative bacilli
→ the only oral antibiotic that can treat pseudomonas aeruginosa
Gram positive
Mycobacteria
Atypical Pneumonia

What are the most important adverse effects associated with Fluoroquinolones?

Tedinopathy and Cartilage Injuries

What is Rifampin?

Antibiotic that inhibits mRNA synthesis of bacteria by blocking DNA dependent RNA polymerase
→ a strong inducer of cytochrome p450 enzymes, causes an increase in elimination of other drugs
→ used in tuberculosis therapy
→ typically always used in combination with other drugs in order to prevent resistant mutants

What are the most important side effects of Rifampin?

Orange urine, tears, and sweat
→ at toxic levels, similar to all cytochrome p450 inducers, it can cause hepatitis and jaundice

What is Metronidazole?

Antibiotic that works by using bacterial nitroreductase which will reduce Metronidazole
→ causes the creation of a free radical that produces damage within the bacteria
→ used to treat anaerobic bacteria

What is the most common side effects of Metronidazole

Causes a metallic taste in their mouth as well as a Disulfiram-like reaction with alcohol

What are Antimetabolites?

Antibiotics that compete with p-aminobenzoic acid, preventing the synthesis of folic acid required by bacteria
→ includes Trimethoprim and sulfamethoxazole

What is Trimethoprim

A Inhibitor of folic acid synthesis by competitively inhibiting dihydrofolate reductase
→ blocks conversion of folic acid to folinic acid which is needed for purine synthesis and ultimately DNA synthesis

What is the spectrum of activity for Trimethoprim and sulfamethoxazole?

Effective against gram positive and gram negative organisms
→ good at fighting Listeria

What are the adverse effects of Trimethoprim-sulfamethoxazole?

Hypersensitivity
→ Stevens-Johnson Syndrome a Type IV hypersensitivity - looks like severe burns across the body and extends onto mucosal membranes

Nephrotoxicity

Displaces unconjugated fetal bilirubin
→ contraindicated in 3rd trimester pregnancy and newborns

What is Pyrazinamide? What is the adverse effect?

Converted to active form pyrazinoic acid by myobacterial enzymes
→ active drug will be taken up to macrophages and acts against mycobacteria that are hiding within the lysosome
→ has hepatotoxicity (worst one)