27. Antimicrobial Drugs - Blocking Bacterial Metabolism

Why are folate inhibitors considered important antibacterial agents?

They inhibit folic acid production, a pathway essential for bacteria but absent in humans, making it a selective target.

What precursor do bacteria use to synthesize folic acid?

Para-aminobenzoic acid (PABA), along with pteridine and glutamate.

What is the spectrum of activity for folate inhibitors?

Effective against Gram-positive and Gram-negative pathogens.

What is the mechanism of action of sulfonamides?

They are structural analogs of PABA and block incorporation of PABA into dihydropteroic acid, inhibiting folic acid synthesis.

What is the mechanism of action of trimethoprim?

It inhibits dihydrofolate reductase (DHFR), preventing conversion of dihydrofolate to tetrahydrofolate. (Selective because trimethoprim has much lower affinity for human DHFR.)

Are sulfonamides and trimethoprim bacteriostatic or bactericidal when used alone?

Bacteriostatic individually; bacteria must use up existing folic acid before growth inhibition occurs.

What drugs make up the combination known as Bactrim, and why are they used together?

Sulfamethoxazole + Trimethoprim; they work synergistically by blocking two sequential steps in folic acid synthesis.

What is the effect of combining sulfamethoxazole and trimethoprim compared to using them alone?

The combination is bactericidal, whereas each drug alone is bacteriostatic.

What are the adverse effects of Bactrim?

Contraindicated in individuals with a sulfa allergy.

What was the original clinical use of quinolones?

Treatment of urinary tract infections (UTIs).

What is the MOA of Fluoroquinolones?

Block function of two bacterial enzymes that repair DNA or aid in division.

Which bacterial enzymes are inhibited by fluoroquinolones, and what is their role?

• DNA gyrase (Topoisomerase II): Relaxes positively supercoiled DNA for replication and transcription.

• Topoisomerase IV: Separates replicated chromosomal DNA into daughter cells during cell division.

What is the consequence of inhibiting DNA gyrase and topoisomerase IV?

DNA replication and transcription cannot occur, leading to bacterial cell death.

Why do fluoroquinolones selectively target bacteria without harming human cells?

Bacterial topoisomerases are structurally different from human enzymes, so human enzymes are not affected.

What makes fluoroquinolones unique among antibacterial classes?

They are the only class that directly inhibits DNA replication by targeting bacterial topoisomerases.

What is the general spectrum and clinical use of fluoroquinolones?

Broad-spectrum (Gram-positive & Gram-negative); used for genitourinary (GU), respiratory, gastrointestinal (GI), and some skin/soft tissue infections.

How does bacterial resistance to fluoroquinolones develop?

Through mutations in DNA gyrase or Topoisomerase IV, reducing drug binding.

What are the adverse effects of fluoroquinolones?

• GI symptoms: anorexia, nausea, vomiting, and abdominal discomfort

• Headache, dizziness, insomnia, and rash

• Risk of mental health side effects and serious blood sugar disturbances 

What is Ciprofloxacin (Cipro)?

A Fluoroquinolone that inhibits bacterial DNA replication. 

What is Levofloxacin (Levaquin)?

A Fluoroquinolone that inhibits bacterial DNA replication. 

Why are mycobacteria inherently resistant to many antibiotics?

• Slow growth rate

• Ability to go dormant

• Lipid-rich cell wall (impermeable to many drugs)

• Drug-degrading/modifying enzymes

• Intracellular location within macrophages (inaccessible to lipophobic drugs)

How does the intracellular lifestyle of mycobacteria contribute to antibiotic resistance?

They reside inside macrophages, making them inaccessible to drugs that cannot penetrate host cells.

Why does treatment of mycobacterial infections require prolonged therapy?

Mycobacteria are very slow-growing, so therapy must continue for months to eradicate infection and prevent resistance.

Why is combination therapy essential in tuberculosis treatment?

To prevent emergence of resistant strains, therapy uses 4-5 drugs simultaneously.

What is the standard treatment regimen for tuberculosis?

• Initial phase (2 months): Isoniazid, Rifampin, Pyrazinamide, Ethambutol

• Continuation phase (4 months): Isoniazid + Rifampin

How is TB therapy adjusted if resistance or poor response occurs?

By increasing duration or changing the drug cocktail based on culture and sensitivity results.

What is the mechanism of action of isoniazid?

Inhibits synthesis of mycolic acids, which are essential components of the mycobacterial cell envelope.

Why is isoniazid effective against both extracellular and intracellular TB organisms?

It penetrates macrophages, allowing activity against intracellular mycobacteria.

How does pharmacogenomics affect isoniazid metabolism?

Metabolized mainly by acetylation; fast acetylators have a shorter half-life, while slow acetylators have prolonged exposure.

What are the major adverse effects of isoniazid?

Hepatotoxicity and peripheral neuropathy.

What is the mechanism of action of rifampin?

Blocks prokaryotic RNA polymerase, preventing initiation of transcription → bactericidal.

What is rifampin’s antimicrobial activity?

Active against Mycobacterium tuberculosis, several Gram-positive and a few Gram-negative bacteria.

What are the major adverse effects of rifampin?

Hepatotoxicity and red-orange discoloration of urine, feces, saliva, sweat, and tears (can stain contact lenses).

How does resistance to rifampin develop?

Rapid, via a single-step mutation altering the RNA polymerase subunit.

What is the mechanism of action of pyrazinamide?

It is taken up by macrophages and disrupts mycobacterial cell membrane metabolism and transport functions, making it effective against intracellular organisms.

Why is pyrazinamide particularly useful in TB therapy?

It is especially effective against intracellular mycobacteria residing in macrophages.

What are the major adverse effects of pyrazinamide?

• Hepatotoxicity

• Nausea and vomiting

• Hyperuricemia (increased serum uric acid; can rarely cause gout)

What is the mechanism of action of dapsone?

It is a structural analogue of PABA and acts as a competitive inhibitor of folic acid synthesis.

What is the primary clinical use of dapsone?

Drug of choice (DOC) for leprosy treatment.

How is leprosy treated based on bacterial load?

• Low load: Dapsone + Rifampin

• High load: Dapsone + Rifampin + Clofazimine
  (Treatment lasts 6–12+ months.)

What are the major adverse effects and resistance concerns with dapsone?

• GI upset: nausea, vomiting, abdominal pain

• Drug resistance is becoming more severe.

What is the clinical role of clofazimine in leprosy treatment?

Used with rifampin and dapsone for leprosy; given as an alternative when dapsone cannot be tolerated.

What is the mechanism of action of clofazimine?

Believed to bind bacterial DNA, inhibiting proliferation; also sequesters in macrophage lysosomes (ion-trapping), making it effective against intracellular M. leprae.

What are the major adverse effects of clofazimine?

• Skin discoloration (red-brown to nearly black; reversible but takes months to years)

• GI intolerance