Medsci 202 - Antibiotics

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Antibiotic

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→ "produced by micro-organisms, effective for killing or inhibiting the growth of other micro-organisms"
→ synthetic antibiotics have been produced now
→ antibiotics don't work against viruses

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Origin of Antibiotics

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1. organic - isolated from bacteria or fungi (penicillin, erythromyocin)
2. semi-synthetic - further derivation of organic compound for greater efficacy (ampicillin, methicillin, oxacillin)
3. generated in lab (sulfonamides, quinolones)

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Antibacterial Spectrum

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→ range of activity against bacteria (broad or narrow)
1. Narrow Spectrum - only effective against a limited variety of bacteria e.g. vancomyocin (works only against gram +ve bacteria)
2. Broad Spectrum - works against a variety of bacteria e.g. ampicillin or tetracyclin (works against both gram +ve and -ve bacteria)

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Bacteriostatic Activity

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→ level of antimicrobial activity that inhibits growth of organism = doesn't have to necessarily kill bacteria, just allows immune response to overpower it

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Bactericidal Activity

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→ level of antimicrobial activity that kills the organism

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Antibiotic Combination

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→ different antibiotics are sometimes combined 'broaden' the antimicrobial spectrum = treat polymicrobial infections and prevent emergence of resistant organism e.g. Mycobacterium tuberculosis

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Antibiotic Synergism

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→ enhanced antimicrobial activity of combined drugs compared to activity of an individual antibiotic = synergistic effect
e.g. penicillin + streptomyocin

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Antibiotic Antagonism

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→ activity of one antibiotic interferes with activity of another = resulting in less activity than the most active individual drug
e.g. penicillin-cholamphenicol

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Antibiogram

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→ shows sensitivity of an isolated strain to different antibiotics

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Kirby-Bauer Method

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→ semi-quantitative method based on diffusion of the antibiotic from a filter disc:
1. discs are saturated with antibiotics
2. greater radius of bacteria to the disc the more effective the antibiotic is
→ concentration gradient around the discs
→ can calculate MHC from diameter

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Minimum Inhibitory Concentration (MHC)

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→ minimum concentration of an antibiotic to inhibit growth of a given bacterium

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Minimum Bactericidal Concentration (MBC)

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→ minimum concentration of an antibiotic to kill a given bacterium
→ MBC is reached when colony forming units (CFU) are reduced to 99.9% below control

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Quantitative Dilution Series

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→ vials of varying antibiotic concentrations, with the last vial having the highest antibiotic conc = no bacterial growth
→ minimum amount of antibiotic conc. required to prevent bacterial growth is MIC
→ MBC can be determined by sub-culturing the clear broth onto antibiotic free solid media

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Basic sites of Antibody Activity

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→ Cell wall synthesis, RNA synthesis, DNA replication, Antimetabolites, Protein synthesis (50S ribosomes), Protein Synthesis (30S ribosomes)

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Antimetabolites

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→ special antibiotics that interfere with bacterium metabolics (bacterial enzymes), therefore inhibiting and killing them

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β-Lactam Antibiotics

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→ inhibits peptidoglycan (cell wall synthesis) synthesis via irreversible inhibition of peptidyl transferase (creates peptide cross links) this inhibition is via PBP (penicillin binding protein)
e.g. penicillin, ampicillin, amoxicillin, carbapenems and cephalosporins (bactericidal)

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β-Lactamase

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→ present in some bacterial strains to allow for resistance to penicillin
→ β-Lactamase = penicillinase, cephalosporinase; they inactivate/destroy the beta lactam ring
→ methicillin, oxacillin and flucloxacillin are unaffected by β-Lactamase
→ clavulanic acid, augmentin = β-Lactamase inhibitor

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Glycopeptides

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→ inhibits peptidoglycan synthesis (cell wall synthesis) by binding to the peptides of the peptidoglycan monomers = weak cell wall + osmotic lysis
→ mainly against gram +ve and acts as a drug 'last resort' e.g. vancomyosin

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Why are gram negative bacteria resistant to Penicillin?

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→ penicillin cannot pass through the bacterial outer membrane, therefore broaden spectrum via semi-synthetic antibiotics e.g. amoxicillin, ampicillin

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Rifamycins

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→ inhibit bacterial RNA polymerase and transcriptase (Rifampin)
→ typically used against Mycobacteria, MRSA and bactericidal

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Quinolones and Fluoroquinolones (Synthetic)

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→ inhibitors of nucleic acid synthesis = bind to DNA topoisomerase e.g. gyrase, topoisomerase IV, helicase
→ they are broad spectrum, bactericidal, used against urinary tract infections, invasive (useful against intracellular bacteria)
→ quinolones (nalidixic acid) are less active than fluroquinolones (ciprofloxacin)

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Sulfonamides and Diaminopyrimidines

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→ they are antimetabolites = prevent the synthesis of tetrahydrofluric acid from para-aminobenzoic acid (PABA)
→ tetrahydrofluric acid is a cofactor needed to make nucleic acids + methionine
→ mammalian cells depend on external folate (B9)
→ sulfonamides work by competitive inhibition, trimethoprim by competitive antagonism
→ they are bacteriostatic, used against urinary tract infections

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Aminoglycosides

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→ inhibit protein synthesis by binding to 30S subunit therefore freezing the 30S initiation complex (30S-mRNA-tRNA) = misreading of DNA
→ effective against aerobic, gram negative bacteria
→ they are bactericidal and synergistic with penicillins
→ e.g. neomycin, gentamycin and kanamycin

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Tetracyclines

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→ targets 30S subunit by inhibiting the binding of aminoacyl-t-RNA to acceptor site on the ribosome = inhibits protein synthesis
→ they are broad spectrum, bacteriostatic and used against many bacterial infections
→ e.g. tetracyclines, doxycyclines

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Macrolides

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→ target 50S subunit by inhibiting translocation of peptidyl tRNA from A to P site = inhibits protein synthesis
→ effective against gram positive and Mycoplasma (no cell wall)
→ bacteriostatic e.g. erythromycin

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Chloraphenicol

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→ targets 50S subunit = inhibit protein synthesis
→ broad spectrum, bacteriostatic antibiotics
→ used only for special case bacterial meningitis = due to toxicity

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Lincosamides

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→ targets 50S subunit by inhibiting peptidyl transferase activity = inhibit protein synthesis
→ they are broad spectrum and bacteriostatic
→ e.g. clindamycin and lincomycin

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Non-genetic (Intrinsic) Antibiotic Resistance

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1. Metabolic inactivity - drugs only affect metabolically active cells, therefore dormant cells are resistant as they are metabolically inactive (don't produce DNA/RNA)
2. Lack of target structure - mycoplasmas lack cell = resistant to penicillin, cephalosporin and vancomycin
3. Exclusion - antibiotic can enter cell e.g. outer membrane of gram negative bacteria are impermeable to penicillin

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Genetic Antibiotic Resistance

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1. Chromosomal resistance - spontaneous mutation in a gene encoding a target receptor = mutation of RNA-polymerase gene result in rifamycin resistance
2. Acquired resistance - via transformation, conjugation or viral transduction

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Antibiotic Resistance Mechanisms

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1. Exclusion of a antibiotic from site of action
2. Efflux pump for antibiotic removal from site of action → specific transport out of cell
3. Enzymatic modification or degradation of the antibiotic → e.g. β-lactamase which breaks lactam ring, others can inactivate wide ranges of β-lactams (extended spectrum β-Lactamase, ESBLs)
4. New or modified antibiotic-insensitive target → MRSA produces PBP2a (altered transpeptidase) with reduced affinity for penicllin

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Multidrug resistant vs. Pandrug resistant

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→ multidrug resistant strains are resistant to more than on class of drugs
→pandrug resistant strains are resistant to all clinically safe drugs