Antibiotics/Antimicrobials

Natural vs. Synthetic vs. Semisynthetic

• Natural/antibiotic -

  • A substance naturally produced by a microorganism that can inhibit the growth of or kill another microorganism

• Synthetic

  • Manufactured entirely in a lab w/ no natural origins

    • 1st synthetic drug → sulfa drugs

• Semisynthetic -

  • Chemically modified derivatives of natural antibiotics

Targets

• Ultimate goal - target pathogen while minimizing host damage

• Target pathogen-specific pathways

  • Cell wall

  • Protein synthesis/ribosomes

  • Cell membrane

  • Metabolism

  • Nucleic acid synthesis

  • Attachment and recognition

Mechanisms of Action

• Interferes w/ Cell Wall Synthesis

  • Penicillin (β-lactams) work to prevent crosslinking of peptidoglycan in cell walls, weakening it and causing lysis

• Interferes w/ Metabolism

  • Target unique pathways like folic acid synthesis

• Inhibits Nucleic Acid Synthesis

  • Rifampicin → inhibits RNA synthesis in gram - and + bacteria

  • Binds to bacterial RNA polymerase and inhibits transcription

  • Gyrase & Topoisomerase IV only in prokaryotic cells

• Damaging Cell Membrane

  • Interferes w/ fatty acid synthesis, distinct in prokaryotes

• Inhibit protein + cell wall synthesis

Bactericidal vs. Bacteriostatic

• Bactericidal:

  • Antimicrobial drugs that actively kill bacteria

  • Targets bacterial cell membranes and nucleic acid

• Bacteriostatic:

  • Their mechanism of action stalls bacterial metabolism and growth without directly causing bacterial death

  • Targets bacterial protein synthesis + metabolic pathways

  • Gives the immune system time to clear the infection

Broad Spectrum vs. Narrow Spectrum

• Broad Spectrum: A wide range of organisms affected

  • Gram + and gram - organisms

• Narrow Spectrum: Few/specific organisms targeted

  • Gram + or mycobacterium only

How do Anti-fungals Work?

• Affect the sterols in the plasma membrane of fungi

  • The principal target is ergosterol - an essential component of fungal cell membranes that determines the fluidity, permeability, and activity of membrane-associated proteins

• Affect fungal cell wall

  • Unique

  • Echinocandins → inhibit the synthesis of glucan for cell wall

• Affect nucleic acid synthesis

  • Flucytosine - Only in fungi, converted to 5-fluorouracil that interferes w/ RNA synthesis

How do Antivirals Work?

• Blocks entrance into host cells

• Interferes w/ reproduction

• Prevents virus protein synthesis

• Stops the virus from assembling viral pieces and from leaving the infected cell

Drug Resistance

• How does it develop?

  • Misuse

    • Overuse

    • Feeding animals antibiotics for growth

    • Antibiotics still prescribed for viral infections

      • Ineffective

• Bacterial Mechanisms:

  • Inactivating/destroying the drug

    • B-lactamases - enzymes that digest penicillin

  • Prevention of drug entry

    • Modify membrane proteins to stop antibiotics from entering

    • Efflux pump

  • Metabolic adaptation

    • Increases concentration of target protein to overcome drug effect

  • Target modification

    • Change target, like 50s subunit, so its no longer susceptible

How do we avoid drug resistance?

• Maintenance of high-concentration

• Proper time frame

• Limitation of distribution

  • Avoid indiscriminate use and in everyday items (soap)

• Use of multiple antimicrobials to inhibit growth without exception

Penicillin

• Interferes with cell wall synthesis

• Belongs to a group of 50 related antibiotics called B-lactams

  • Natural penicillin

  • Semi-synthetic penicillin

• Narrow spectrum

Cephalosporin

• Interferes w/ cell wall synthesis

• Naturally occurring → fungi of the genus Acremonium

• Bactericidal

• Same mode of action as B-lactam but less susceptible to B-lactamases

  • targets cell wall synthesis by inhibiting PBPs that are crucial for peptidoglycan cross linking

• Broad spectrum

Chloramphenicol

• Protein synthesis inhibitor

• Targets 50s subunit

• Inhibits the formation of peptide bonds

• Synthetic, but originally isolated from streptomyces

• Bacteriostatic

• Broad spectrum

Clindamycin

• Protein synthesis inhibitor

• Similar mode of action to Chloramphenicol

• Broad spectrum

• Useful in infections caused by MRSA, most strains of MRSA are still susceptible to Clindamycin

• Rare cases: causes liver damage

Tetracycline

• Protein synthesis inhibitor

• Binds to the 30s subunit and interferes w/ tRNA attachment

• Broad spectrum

• Small amounts can enter mammalian cells - used for bacteria liked Rickettsia & Chlamydia

Erythromycin

• Protein synthesis inhibitor

• Binds to 50s and blocks mRNA movement

• Bacteriostatic

• Similar spectrum to penicillin G

• A macrolide, contains a macrocyclic lactone ring

Rifampicin

• Inhibits Nucleic Acid Synthesis

• Inhibits RNA synthesis by binding to the bacterial RNA polymerase and inhibits transcription

• Broad spectrum