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Questions and Answers
What defines selective toxicity in antimicrobial drugs?
Which type of antimicrobial drug directly kills bacteria?
What is an advantage of broad-spectrum antibiotics?
What may result from the use of broad-spectrum antibiotics?
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What characterizes semi-synthetic antimicrobials?
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What is a key limitation of antimicrobial drugs targeting Gram-negative bacteria?
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What is the primary purpose of antibiotic substances produced by microorganisms?
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What can result from the disruption of normal flora caused by some antibiotics?
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What is a significant risk associated with the use of chloramphenicol?
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For which condition are aminoglycosides primarily used today?
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What is a major side effect of using tetracyclines?
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Which statement about macrolides is true?
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What is the consequence of prolonged use of aminoglycosides?
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What is a potential advantage of monobactams?
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Which statement about cephalosporins is true?
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What is the primary effect of isoniazid?
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Why can protein synthesis inhibitors have toxic effects on humans?
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Which antibiotic is used to treat leprosy by inhibiting nucleic acid synthesis?
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What is the main mechanism of action of aminoglycosides?
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What type of bacteria does ethambutol primarily target?
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Chloramphenicol prevents which of the following during protein synthesis?
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What is a significant side effect of rifampin?
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Which class of antibiotics is effective against intracellular bacteria such as Chlamydia?
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What mechanism do fluoroquinolones utilize to eliminate bacteria?
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How do sulfonamides work in bacterial infections?
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What is the principle behind the synergistic effect of combining penicillin and streptomycin?
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Which antifungal class blocks the synthesis of fungal sterols?
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Why are fluoroquinolones not recommended for children and pregnant women?
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What type of bacteria is polymyxin B primarily effective against?
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What is a potential risk associated with the use of amphotericin B?
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What is the primary mode of action for penicillin?
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What is the common structure found in all penicillins?
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Which type of penicillin is most commonly susceptible to β-lactamases?
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Which antibiotic is commonly used to treat MRSA infections?
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What characteristic differentiates semisynthetic penicillins from natural penicillins?
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What is a major mechanism through which bacteria develop resistance to penicillin?
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What type of bacteria does Vancomycin primarily target?
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What feature of Staphylococcus aureus contributes to its resistance against methicillin?
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Study Notes
Antimicrobial Drugs
- Antimicrobial drugs are used to treat infectious diseases by interfering with the growth of microorganisms
- The ideal drug will kill pathogens without harming the host
- Selective toxicity: attacks some cells but not others, refers to a drug's ability to attack specific microbial cells but leaves other cells unharmed
- Most drugs available are antibacterial, fewer are anti-fungal, anti-protozoan, or anti-helminthic. Anti-viral drugs are the least common.
Definitions and Classification of Antimicrobials
- Antibiotic: substance that inhibits the growth of a microorganism
- Technically, antibiotics are produced by microorganisms but synthetic drugs are also commonly called antibiotics
- Antibiotics can be:
- Bacteriostatic agents, which stop bacterial replication and prevent growth; the host's immune system then eliminates the bacteria
- Bactericidal agents, which kill bacteria directly
Spectrum of Activity
- Range of microbes that an antimicrobial drug can affect
- Narrow-spectrum: works against a limited number of pathogens
- Broad-spectrum: affects a wide range of Gram+ and Gram- bacteria
- Advantages: treats unknown infections and infections caused by different organisms, such as bacterial meningitis
- Disadvantages: can destroy the normal flora of the host, leading to overgrowth of other species (superinfection)
- Examples: C. difficile diarrhea, C. albicans overgrowth, opportunistic growth of antibiotic-resistant strains
- Semi-synthetics: chemically altered antibiotics more effective than naturally occurring ones
- Synthetics: antimicrobials completely synthesized in a lab
Gram Negative Outer Membrane Limits Drug Penetration
- Most antibacterial drugs have polar properties
- Gram Negative bacteria have an outer membrane, composed of a "lipid bilayer" with fatty acid tails, which prevents the passage of polar molecules
- Small, water-filled "pores" allow entry only by compounds soluble in water
- If a drug can’t reach its specific target, it is useless
Type 1: Inhibition of Cell Wall Synthesis
- Bacterial cell walls are distinct from eukaryotic cell walls
- prokaryotic cells have peptidoglycan
- These drugs interfere with synthesis of the cell wall, only affecting actively growing cells
- Weakened cell wall exposes the plasma membrane and leads to lysis
Penicillin
- "Family" of over 50 chemically related antibiotics
- Common core structure: a β-lactam ring found in all penicillins
- Penicillins also called “β-lactam antibiotics”
- Penicillin V was the first penicillin discovered
- Different types of penicillin vary in their R-group
β-lactam Ring Required for Penicillin Activity
- Some bacteria produce β-lactamase, an enzyme that breaks the β-lactam ring and inactivates penicillin
- β-lactamase is also called “penicillinase”
- This is the most common form of penicillin resistance
Natural vs Semisynthetic Penicillin
- Natural penicillins:
- Extracted directly from Penicillium cultures
- Narrow spectrum (G+); useful against most Staphylococci, Streptococci & spirochetes
- Often susceptible to β-lactamases
- Pen G & Pen V are the most common natural penicillins
- Semisynthetic penicillins:
- β-lactam core made by Penicillium
- R-group is added in the lab
- Engineered for specific characteristics:
- Can be designed to be more resistant to β-lactamase (methicillin)
- Can be designed to have a broader specificity: Gram+ & some Gram- (ampicillin, amoxicillin)
Antibiotic Resistance
- Antibiotic resistance is a growing problem:
- MRSA: methicillin-resistant Staphylococcus aureus
- Penicillins usually interact with bacterial cell walls through penicillin binding proteins in the peptidoglycan layer
- MRSA has a genetic mutation that prevents penicillin binding
- MRSA also produces beta-lactamase
- Patients with MRSA infections must be isolated
- MRSA can be treated with vancomycin
Vancomycin
- Named for the word “vanquish”
- Glycopeptide antibiotic: completely different structure than penicillin
- Naturally produced by a species of Streptomyces
- Inhibits cell wall synthesis
- Very narrow spectrum
- Mostly used to treat MRSA
- Recently strains of S. aureus and certain Enterococci species resistant to vancomycin have been discovered
- Toxicity used to be a problem but improved manufacturing procedures have corrected this
Monobactams
- Synthetic and semisynthetic antibiotics
- Potential advantage: not found in nature, therefore takes more time for pathogens to develop resistance
- Structure is similar to penicillin but different enough that it is not sensitive to β-lactamase
- Spectrum of activity:
- Affects certain Gram negative bacteria (E. coli, H. influenzae, P. aeruginosa); effective in treating these infections in Cystic Fibrosis patients
Cephalosporins
- Similar chemical structure to penicillin (β-lactam ring)
- Examples: cephalothin, cefixime
- Comes from the fungus Cephalosporium
- Inhibit cell wall synthesis in the same way as penicillin, but tend to be more broad-spectrum than natural penicillin
- Susceptible to a different group of β-lactamases
Mycobacteria
- Have different cell walls from other bacteria
- M. tuberculosis, M. leprae: cause tuberculosis, leprosy
- Cell walls contain mycolic acids and a small amount of peptidoglycan
- Anti-mycobacterial antibiotics interfere with mycolic acid incorporation or synthesis
- These drugs have minimal to no effect on other bacteria
- Isoniazid: inhibits mycolic acid synthesis
- Ethambutol: inhibits the incorporation of mycolic acid
- Fairly weak on its own, so administered as part of a "cocktail" to prevent development of resistance
- Dapsone (tx Leprosy): inhibits nucleic acid synthesis
Type 2: Inhibition of Protein Synthesis
- Ribosomes are the sites of protein synthesis
- Eukaryotic and prokaryotic ribosomes are different:
- Eukaryotic: 80S ribosomes (40S + 60S subunits)
- Prokaryotic: 70S ribosomes (30S + 50S subunits)
- Targeting 70S ribosomes directs action against bacteria
- Problem: mitochondria have 70S ribosomes, some drugs in this group may have toxic effects on humans
- Protein synthesis inhibitors: drugs in this category all have slightly different modes of action with the same end result
Examples: Mechanisms of Action of Protein Synthesis Inhibitors
- Chloramphenicol: prevents peptide bond formation [50S subunit]
- Aminoglycosides: block initiation and cause misreading of mRNA [30S subunit]
- Tetracyclines: block attachment of tRNA to the ribosome [30S subunit]
- Macrolides: prevent continuation of synthesis (translocation from A site to P site) [50S subunit]
Chloramphenicol
- Broad spectrum
- Simple structure: small size allows it to diffuse into areas inaccessible to many other drugs
- Inexpensive to manufacture, often used where low cost is essential
- Down side: serious toxicity problems
- Suppression of bone marrow activity: aplastic anemia, potentially fatal, affects formation of blood cells, 1 in 40,000 users affected (normal: 1 in 500,000)
- Teratogenic in neonates: causes grey baby syndrome
Aminoglycosides
- Among the first antibiotics found to have activity against Gram- bacteria
- Bactericidal
- Can be toxic, therefore use is declining
- Permanent damage to the auditory nerve (Ototoxicity) and kidneys
- Current use:
- Cystic fibrosis where lung infections with Pseudomonas aeruginosa are common (G-, difficult to treat)
- Tobramycin is delivered as an aerosol to control these infections
Tetracyclines
- Broad spectrum: effective against Gram+ and Gram-, intracellular bacteria
- Able to penetrate tissues and cells well
- Natural protein synthesis inhibitor, but semisynthetics have longer retention in the body (doxycycline, minocycline)
- Uses:
- UTI, Mycoplasma, Chlamydia, and Rickettsia infections
- Alternatives for syphilis and gonorrhea instead of penicillins
- Problems:
- Suppress normal flora (broad spectrum)
- GI upsets leading to superinfections, often by C. albicans
- May cause brown teeth discoloration in children younger than 8 years old
- May cause liver damage in pregnant women
- Suppress normal flora (broad spectrum)
Macrolides
- Narrow spectrum (G+)
- Alternative to penicillin
- Too big to enter G- cells
- Inhibit protein synthesis
- Oral administration:
- Orange-flavored suspension often used to treat streptococcal and staphylococcal infections in children
- Useful to treat people who are allergic to β-lactams
- Erythromycin
- Azithromycin, clarithromycin
- Broader specificity, better tissue penetration
- Important for treatment of intracellular bacteria such as Chlamydia
Type 3: Injury to Plasma Membrane
- Change permeability of the plasma membrane
- Essential metabolites leave the cell
- Probably not the best choice: eukaryotic plasma membrane is very similar to bacteria
- Example: Polymyxin B
- First drug active against gram(-) Pseudomonas
- Attaches to phospholipids, causes disruption
- Host toxicity: significant internally
- Used as a topical treatment for superficial infections
- Available in non-prescription antibiotic ointments: Polysporin
Type 4: Nucleic Acid Synthesis Inhibitors
- May interfere with replication or transcription
- May cause harm to the human host, but useful drugs in this class are more harmful to the bacteria than the host (selective toxicity)
- Rifamycins: most common is rifampin
- Inhibits mRNA synthesis, bactericidal
- Side effect: orange-red urine, feces, tears, sweat, saliva
- Can penetrate tissues:
- Therapeutic levels in CSF and abscesses
- Useful for treatment of TB along with isoniazid & ethambutol - Tissue penetration required
Quinolones & Fluoroquinolones
- Bactericidal, broad spectrum
- Specifically inhibit bacterial DNA replication
- Quinolones: early drug (1960’s), limited use
- Only application: UTI
- Fluoroquinolones: developed in the 1980’s
- Norfloxacin, ciprofloxacin (Cipro)
- Safe for adults, but not recommended for children, adolescents, or pregnant women:
- Affects cartilage development
- New synthetic versions being developed that are broader spectrum, but adversely affect some drugs that control heart rhythm
Type 5: Drugs that Inhibit Metabolic Pathways & Enzymatic Activity
- It is possible to block the activity of essential enzymes within a cell using specifically designed drugs
- Competitive inhibition: a drug with a very similar structure to the normal substrate can "block" the active site of an enzyme, preventing it from carrying out its normal function
Sulfonamides
- Sulfa drugs (among the first synthetic antimicrobials)
- PABA (para aminobenzoic acid): required to make nucleic acids in pathogens, but not in humans
- Most widely used today:
- TMP-SMZ (trimethoprim & sulfamethoxazole): synergistic combo
- Broad spectrum
- Used for control of pneumonia caused by Pneumocystis carnii
- Effective in penetration of the brain & CSF
Things to Consider in Combining Drugs
- Synergism: when 2 drugs used together are more effective than either one alone
- Penicillin (damage cell wall) + streptomycin (inhibit protein synthesis at the ribosome)
- Damage by penicillin allows entry by streptomycin
- Penicillin (damage cell wall) + streptomycin (inhibit protein synthesis at the ribosome)
- Antagonism: when the activity of one drug works against the activity of another when they are used together
- Penicillin (inhibits ACTIVE cell wall synthesis) + tetracycline (stops bacterial growth) - Bacteria that are not making a cell wall are not affected by penicillin
Antifungals
- Fungal infections are increasing in frequency: opportunistic infections, immunosuppression, AIDS
- Toxicity problem since fungi are eukaryotes
- Azoles: block fungal sterol synthesis
- Clotrimazole, miconazole (Monistat): topical treatment of athlete’s foot, yeast infection
- Triazoles: less toxic, but still some liver damage - Fluconazole, ketoconazole: treatment of systemic mycoses
- Polyenes: kills fungal cells via sterol recognition
- Amphotericin B commonly used treatment for systemic mycoses
- Toxicity in the kidney limits use
Antivirals & Antiviral Targets
- In the developed world many of the most serious infections are caused by viruses, but there are few antiviral drugs
- Ideally, drugs that kill pathogens without harming the host, but this is difficult when dealing with cellular hijackers
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Description
Explore the essential concepts behind antimicrobial drugs, including their classifications and modes of action. This quiz covers antibiotics, selective toxicity, and the spectrum of microbial activity. Test your knowledge on how these drugs combat infections effectively.
