Chapter 20 Antimicrobial Drugs

Metronidazole

• Affects: Protozoa and strict anaerobes

• Interferes with anaerobic metabolism

Mendazole

• Affects: Helmimths

• Inhibits formation of microtubules in the cytoplasm which blocks absorption of nutrients by helminths

Praziquantel

• Affects: Helminths

• Kills by altering the permeability of the plasma membrane

What are some features of Antimicrobial drugs?

• Selective toxicity

• Antimicrobial Action

• Tissue Distribution and metabolism

Selective Toxicity

To be able to killa microbe without harming the host.

Bacteriostatic vs Bactericidal Antimicrobial Action

The microbe will be inhibited while the microbes are killed.

Broad Spectrum vs Narrow Spectrum Antimicrobial Action

• Many different microbes versus a few

Tissue Distribution and Metabolism of Antimicrobial Drugs

This is the drug’s half-life in the body.

Intrinsic Microbial Resistencem

• A drug that has no effect on the microbe

  • Ex: Penicillin will only target microorganisms that have peptidoglycan. Innefective against viruses

Acquired Microbial Resistance

• Due to a mutation or new genetic element.

  • Through transformation, conjugation, and transduction, microorganisms can gain new genes like R-factor plasmids.

How can Microbes become resistant?

1. Block Entry

   • Using porins (proteins on cell wall)

2. Inactivation by Enzymes

   • Beta-lactamase which can inactivate penicillin

3. Alteration of Target Molecule

   • Mutations in the HIV protein being targeted by drugs.

4. Efflux of antibiotic

   • The drug is being pumped out through efflux pumps like Pseudomonas

How do physicians and healthcare workers prevent and control antibiotic resistance?

• Proper prescribing practices

• Patient Education

How do patients prevent and control antibiotic resistance?

• Follow instructions; take dosages at a proper time; complete entire course of antibiotic

How does the public prevent and control antibiotic resistance?

• Understand limitations of antibiotics

Modes of Action by Antibiotics

• Inhibit cell wall synthesis

  • Penicillins, cephalosporins, bacitracin, vancomycin

• Inhibit protein synthesis

  • Chloramphenicol, erythromycin, tetracylines, streptomycin

• Injure the plasma membrane

  • polymyxin B

• Inhibit nucleic acid synthesis (DNA/RNA)

  • quinolones, ritampin

• Inhibit synthesis of essential metabolites (inhibit specific metabolic pathways)

  • Sulfanilamide, trimethoprim

Penicillins

• Natural - Produced by penicillium

  • Penicillin G and Penicillin V

• Prevents synthesis of peptidoglycan

  • Gram Positive cells are more susceptible → narrow spectrum

• Some bacteria are resistant because they can produce penicillinase

  • B-lactamase breaks down the B-lactam ring of penicilin which inactivates it

Semisynthetic Penicillins

• Produced to be Resistant to β-lactamases

  • Methicillin

  • Oxacillin

    • MRSA Methicillin-Resistant S. aureus is resistant to this.

• Extended Spectrum (broad)

  • Ampicillin, amoxicillin

  • Carbenicillin, ticarcillin

Penicillin plus B-lactamase inhibitor

• Clavulanic acid is a β-lactamase inhibitor (non-competitive inhibitor)

  • Inhibits beta-lactamase

Cephalosporins

• Works similar to Penicillin but has a different type of beta lactam ring

Polypeptide Antibiotics

• Bacitracin

• Vancomycin

  • Used to treat MRSA

Antibmycobacterial

• Isoniazid (INH)

  • Inhibits mycolic acid

• Ethambutol

  • Inhibits the integration of mycolic acid in the cell wall.

• Effective against Mycobacterium

What are some antibiotics that will inhibit protein Synthesis?

• Chloramphenicol

• Aminoglycosides

• Tetracyclines

• Macrolides

• Chloramphenicol

• Binds 50S ribosome, inhibits peptide bond formation

• Broad Spectrum

Aminoglycosides

• Binds 30S ribosome, causes mRNA to be read incorrectly

• Broad Spectrum

• Example: Streptomycin, gentamicin, neomycin

Tetracyclines

• Bind to 30S ribosome, block incoming tRNA

• Broad spectrum

• example: Tetracycline, doxycycline

Macrolides

Bind 50S ribosome, block continuation of protein synthesis
– example: Erythromycin, azithromycin, clarithromycin, telithromycin

Injury to Membranes

Affects synthesis of bacterial plasma membranes

Lipopeptides

Daptomycin

• Attacks the bacterial cell membrane

Polymyxin B

• Topical; bacteriocidal; effective against gram-negatives

• Combined with bacitracin and neomycin in nonprescription ointments

Antibiotics that Inhibit Nucleic Acid Synthesis

• Rifamycin

• Quinolones and Fluoroquinolones

Rifamycin

Inhibits RNA polymerase to block synthesis of mRNA

Quinolones and Fluoroquinolones

– Inhibits DNA replication
– example: Ciprofloxacin (Cipro)

Sulfonamides (sulfa drugs

Interfere with different enzymes needed in the metabolic pathway for
making tetrahydrofolic acid (a precursor for proteins, DNA, and RNA)
– example: TMP-SMZ = trimethoprim + sulfamethoxazole
– Drug synergism

Drug synergism

the interaction between two or more drugs where their combined effect is greater than the sum of their individual effects when each is administered alone.

Antiviral Drugs Mechanism of Action

1. Nucleoside and nucleotide analogs

2. Inhibit viral enzymes or proteins

3. Interferons

What are examples of ways to inhibit viral enzymes or proteins?

1. Reverse transcriptase (RT) inhibitors

2. Protease inhibitors

3. Integrase inhibitors

4. Neuraminidase inhibitors

5. Entry and Fusion inhibitors

Function of the Antiviral Drug Acyclovir

It works by stopping the virus from replicating and spreading in the body, which helps relieve pain, speed up healing of sores, and reduce the risk of complications. 

What does Acyclovir mimic?

Nucleoside.

Acyclovir acts as a nucleoside analog ("doppelganger") that…

tricks thymidine kinase into creating a false nucleotide that BLOCKS DNA polymerase and STOPS DNA synthesis.

1. RT inhibitor - non-nucleoside RT inhibitor

Inhibit viral dsDNA but does NOT resemble a nucleoside

Targets enzyme Reverse Transcriptase

2. Protease inhibitor

Ritonavir prevent the maturation of HIV

Paxlovid (for Covid) prevents the synthesis of RNA-dependent RNA polymerase 

3. Integrase inhibitor

Prevent creation of a provirus in HIV

Neuraminidase inhibitor

Prevents release of Influenza virions

Fusion/Entry inhibitors

Prevent fusion and entry of virus into host cell

: Acyclovir, famciclovir, and ganciclovir 

 Nucleoside analog

       – Herpes simplex viruses

       – Inhibit DNA replication

Zidovudine (AZT)

 Nucleoside RT (Reverse Transcriptase) inhibitors

       –  HIV

       – Inhibit DNA synthesis

Interferons as Antiviral Drugs include…

example: α-IFN (IFN-α) used to treat hepatitis

• example: Imiquimod, stimulates the production of IFN-α ➡ Antiviral Proteins (AVPs) that prevent viral replication

Antifungals that target the plasma membrane

 Plasma membranes of fungi/ animals contain:

        – Fungi: ergosterol

         – Animals: cholesterol

Antifungals that inhibit synthesis of ergosterol:

Polyenes

       • example: amphotericin B

• Azoles

• example: clotrimazole, miconazole, fluconazole

Antifungal drugs that inhibit synthesis of ergosterol in fungal plasma membranes include

• Polyenes like Amphotericin B

• Azoles like Micoazole

Animal plasma membranes typically contain cholesterol, whereas fungi plasma membranes typically contain_____.

Ergosterol

Acyclovir (antiviral)

Nucleoside analogue that “tricks” thymidine kinase

Imiquimod (antiviral)

Stimulates the production of IFN-alpha

Paxlovid (antiviral)

Protease inhibitor that inhibits the formation of RNA-dependent RNA polymerase

Ritonavir (antiviral)

Protease Inhibitor that prevents HIV maturation