Antibiotics

Question 1

Describe the concepts of selective toxicity in relation to antibiotics

Answer 1

Principles of Antibiotics as Therapeutic Agents:

1) Selective Toxicity:

refers to the ability of a drug to selectively kill or inhibit the growth of microbial targets while causing minimal or no harm to the host

• Due to the differences in structure and metabolic pathways between host and pathogen
• Harm microorganisms, not the host
• Target in microbe, not host (if possible)
• Difficult for viruses (intracellular), fungi and parasites
• Variation between microbes
• Effect on commensals

2) Therapeutic Margin:

• Active dose (MIC) vs Toxic effect

Selective toxicity examples:

1) Beta-Lactam Antibiotics (Penicillins):

• These antibiotics target the bacterial cell wall, a structure that human cells lack
• inhibit enzymes (penicillin-binding proteins) involved in peptidoglycan synthesis, a key component of the bacterial cell wall; osmotic lysis

2) Glycopeptide Antibiotics (Vancomycin):

• glycopeptides inhibit cell wall synthesis via binding directly to peptidoglycan precursors
• preventing their incorporation into the growing cell wall

3) Macrolide Antibiotics (Erthromycin):

• target the bacterial ribosome, specifically the 50S subunit, and inhibit protein synthesis
• Bacterial ribosomes are 70S (50S + 30S subunit) whereas human ribosomes are 80S (60S +40S subunit)
• The difference in ribosome structure allows macrolides to selectively inhibit bacterial protein synthesis

4) Aminoglycosides (Gentamicin, Streptomycin):

• Target 30S subunit of the bacterial ribosome, interfering with protein synthesis

Question 2

Define the biological and pharmaceutical origins of antibiotics

Answer 2

Biological Origins:

compounds produced by microorganisms; advantage to the producing organism by inhibiting the growth of competitors

• Bacterium-derived antibiotics Streptomyces (actinomycetes genus)
• Fungus-derived antibiotics: Penicillin

Pharmaceutical Origins:

chemically modify naturally occurring antibiotics to improve its efficacy, safety, or spectrum of activity

• Semi-synthetic antibiotics: methicillin, ampicillin, and amoxicillin are chemically modified semi-synthetic penicillin that are more effective against a broader range of bacteria or more resistant to bacterial mechanisms of resistance
• Fully synthetic antibiotics: fluoroquinolones (ciprofloxacin, levofloxacin), are fully synthetic, designed and created entirely in the lab. Developed based on the knowledge of bacterial targets such as DNA gyrase and topoisomerase IV

Question 3

Define the terms: bactericidal, bacteriostatic, broad and narrow spectrum, MIC

Answer 3

1) Bactericidal:

• Directly kill bacteria by interfering with bacterial cell wall synthesis, DNA replication, or protein production, e.g. penicillin and ciprofloxacin

2) Bacteriostatic:

• inhibit the growth or multiplication of bacteria by interfering with bacterial protein production, DNA replication, and bacterial cellular metabolism

3) Broad Spectrum:

• effective against a wide range of both Gram-positive and Gram-negative bacteria
• useful when it is not possible to determine the specific type of bacterium causing an infection
• also used in treating mixed infections and preventing infections in patients with weakened immune systems. E.g. amoxicillin and ciprofloxacin

4) Narrow Spectrum:

• effective against a select group of bacterial types, only gram +ve/-ve or only against a specific genus of bacteria
• cause less disruption to the normal microbiota. E.g. dicloxacillin and azithromycin

MIC (Minimum Inhibitory Concentration):

• the lowest concentration of an antimicrobial agent that prevents the visible growth of a microorganism in vitro (in a test tube or petri dish)
• The MIC is used in diagnostic laboratories to determine the susceptibility of microorganisms to different antibiotics
• Antibiotics with low MICs are more effective than those with higher MICs
• This helps clinicians choose the most effective antibiotic to treat a particular infection

Question 4

Describe the categories of antibiotics, their modes of action, and targets, giving a named example of an antibiotic for each category

Answer 4

1) Cell Wall Synthesis Inhibitors:

• preventing the formation of the bacterial cell wall; osmotic lysis
• E.g. Penicillin - inhibit the final cross-linking of peptidoglycan chains

2) Protein synthesis inhibitors:

• inhibit bacterial protein synthesis, affecting the bacterial ribosomes without harming human ribosomes due to structural differences
• E.g. Erythromycin - bind to the 50S subunit, preventing elongation

3) Folic Acid Synthesis Inhibitors:

• These antibiotics interfere with the synthesis of folic acid, a critical nutrient for bacteria; inhibiting DNA, RNA, and protein synthesis
• E.g. Sulfonamides: structural analogues of para-aminobenzoic acid (PABA), a precursor for folic acid synthesis

4) Metabolic Pathway Inhibitors:

• hinder certain metabolic pathways vital to the bacteria’s survival
• E.g. Quinolones (e.g., ciprofloxacin): inhibit bacterial DNA gyrase and topoisomerase IV, which are crucial enzymes for bacterial DNA replication, transcription, repair, and recombination

5) Cell Membrane Disruptors:

• disrupting the bacterial cell membrane, causing cell contents to leak out, leading to cell death
• E.g. Polymyxins: bind to the bacterial cell membrane, altering its structure and leading to increased permeability, leakage of cellular contents, and cell death, particularly Gram-negative

Question 5

Explain in broad principles when antibiotics are used and how they are delivered

Answer 5

When Antibiotics are used:

1) Treatment of bacterial infections:

• Antibiotics are typically prescribed when a patient has a confirmed bacterial infection, such as pneumonia, UTI, skin infections
• antibiotic selected is usually based on the type of bacteria causing the infection, as determined by microbiological testing, along with the patient’s overall health status

2) Prophylactic use:

• Antibiotics can also be used to prevent infections, particularly in certain at-risk populations
• This includes patients undergoing surgery (to prevent post-operative infections), patients with certain types of heart disease before dental procedures (to prevent bacterial endocarditis), and people exposed to a person with a bacterial infection that can easily spread, such as meningitis

3) Empiric Therapy:

• When the exact cause of an infection is unknown, but a bacterial cause is suspected, empiric therapy may be started
• based on the types of bacteria that are most likely causing the infection and local resistance patterns

How Antibiotics are Delivered:

1) Orally:

• in the form of tablets, capsules, or liquid suspensions. The medication is then absorbed through the digestive system

2) Intravenous (IV):

• For severe infections or in cases where the patient cannot take oral medications
• This allows for rapid and complete absorption of the drug into the bloodstream

3) Topical:

• For skin and eye infections, antibiotics may be applied directly to the affected area in the form of creams, ointments, or eye drops

4) Intramuscular:

• Some antibiotics, such as penicillin, may be given as an intramuscular injection. This is less common than oral or intravenous routes

5) Inhalation:

• Certain antibiotics can be given by inhalation, especially for respiratory infections in cystic fibrosis patients