Roger micro

• Therapeutic dose


  Level for successful treatment of infection
• Toxic dose


  Level at which agent is too toxic for host
• Therapeutic index / window

  Selective toxicity (over-simplification)
• Drugs that disrupt microbial functions not found in eukaryotic cells


  • Greater selective toxicity
  • Greater therapeutic index
  • (not all adverse effects are due to the primary mechanism of action)
• Cell wall synthesis


  Linking together of NAM subunits by connecting their peptide chains is facilitated by family of enzymes (transpeptidases)
• Penicillin Binding Proteins (PBPs)


  Also known as transpeptidase (therapeutic target and biochemical activity used interchangeably)
• How PBPs work


  Peptidoglycan X-linking
• β-lactams


  • Essential core = β-lactam ring
  • Mechanism of action is essentially same for all: Bind and inhibit PBPs (note: PBP subtypes exist)
  • β-lactam ring resembles D-alanyl-D-alanine portion of peptide side chains
  • Transpeptidase (PBP) irreversibly binds with lactam and not side chain
  • Disruption of peptidoglycan crosslinking (generally considered bactericidal - lysis)
• Lactam / β-lactam ring


  • Lactam = lactone + amide (Greek letter indicates size)
  • Lactone: cyclic carboxylic ester
  • β 4-atom, γ 5-atom, δ 6-atom, ε 7-atom
  • Bond-angle in a 4-membered ring is strained (reactive)
• 1. ala D-ala at end of pentapeptide chain
• Resistance


  • Intrinsic resistance
  • Acquired resistance
• Penicillins - subgroups


  • Natural penicillin (Penicillin G, Penicillin V)
  • Antistaphylococcal penicillins (flucloxacillin, methicillin, etc)
  • Aminopenicillins (amoxicillin, ampicillin)
  • Extended-spectrum penicillins (piperacillin, ticarcillin, etc...)
• Penicillin / β-lactamase inhibitor combinations


  • amoxicillin-clavulanate (augmentin)
  • piperacillin-tazobactam (tazocin)
  • additional lactams as "decoy" substrate
• β-lactamase inhibitors (mechanisms)


  • Reactive molecule with high tendency to bind to β-lactamases
  • Thus, active antibiotic doesn't get cleaved
  • Increased activity against G+ / G- / anaerobes
• Cephalosporins (Cefalosporins)


  • Cephalosporium (now Acremonium)
  • Nucleus + 2 main side chains (R1, R2)
  • "more" resistant to β-lactamases (not immune)
  • 2 major sites are modified: R1 for antibacterial activity including changes water solubility and PBP affinity, R2 for pharmacokinetic properties
• Cephalosporins: first generation


  • cefalexin
• Cephalosporins: second generation


  • cefuroxime
• Cephalosporins: third generation


  • ceftazidime
  • ceftriaxone
• Cephalosporins: third generation


  • R1 Polar: Increased porin penetration
  • Increased affinity for some PBPs
  • Increased stability vs. G- β-lactamases
  • ceftazidime active against Pseudomonas
  • R2 - ceftriaxone has a long half life
• Cephalosporins: fourth+ Generation


  • cefepime (4th)
  • ceftaroline (5th)
• Carbapenems


  • Imipenem
  • meropenem
  • ertapenem
• Carbapenems


  • VERY broad (G+, G-, Anaerobes)
  • Imipenem, meropenem also against Pseudomonas
  • Stable to many "normal" penicillinases (not to KPC and NDM among others)
  • Low risk for penicillin allergy
• Monobactams


  • aztreonam
  • Narrow spectrum: aerobic G-
  • Lone β-lactam ring
  • Totally synthetic
  • Combines advantageous properties from 3G cephalosporins
  • Very low likelihood of reaction in penicillin-allergic patients (but R1 chain is very like ceftazidime)
• Glycopeptides


  • vancomycin (also teicoplanin)
  • Origin - Streptomyces organisms
  • Inhibit cell wall synthesis by forming a complex with the substrates that make up peptidoglycan (D-ala-D-ala)
  • Narrow-spectrum, restricted to G+ bacteria (too big to penetrate the porins of G- cells)
  • "slowly/weakly" bactericidal
• Fosfomycin


  • Origin - Streptomyces organisms
  • Usually for uncomplicated UTIs
  • Broad-spectrum against G+ and G-
  • "slowly/weakly" bactericidal
  • Inactivates MurA (inhibits peptidogylcan synthesis)
  • Fosfomycin resistance enzymes are in existence on chromosome and transferrable plasmids (FosA / FosB / FosX)
• Bacitracin


  • Origin – Bacillus subtilis organism
  • Interferes with peptidoglycan synthesis
  • Narrow-spectrum, usually for G+ organisms that cause skin infections
• Cell Envelope Disruptors


  • daptomycin "Inserts" into Gram-POSITIVE cell membrane, aggregates, causing leakage of ions from within and major disruption of cell function. BACTERICIDAL
  • colistin Attaches to lipopolysaccharide and phospholipid in Gram-NEGATIVE cell membrane, causing leakage of ions from within and major disruption of cell function. BACTERICIDAL
• Protein synthesis inhibitors


  • Bacteria must constantly produce new biomolecules to Replace / repair "used" or secreted functional & structural proteins and peptides
  • Build / grow new bacteria within a population
  • Not possible without fresh protein synthesis
• Protein synthesis inhibitors


  • Many antibiotics bind more avidly to the prokaryotic ribosome (30S/50S vs 40S/60S)
  • Binding can be to 30S (small) or 50S (large) ribosomal subunit (these are further subdivided)
  • Other antibiotics inhibit other steps in synthesis: aminoacyl-tRNA binding, peptide bond formation, mRNA reading, translocation
• Aminoglycosides


  • 2+ amino sugars and an aminocyclitol (C6) ring
  • Broad-spectrum: usually aerobic G- rods and certain G+
  • Bind to 30S ribosomal subunit (interferes with translational proofreading)
  • Interfere with protein synthesis by directly inhibiting, causes misreading of the messenger RNA – "false" proteins produced
  • Bactericidal – unusual for protein inhibitors
• Aminoglycosides: Examples


  • gentamicin
  • tobramycin, amikacin
  • streptomycin
• Macrolides


  • Contain 12 to 22-carbon lactone rings linked to one or more sugars
  • e.g. erythromycin
  • Moderate-spectrum, usually bacteriostatic
  • Binds to 23S rRNA of 50S ribosomal subunit and inhibits peptide chain elongation
  • Often used in penicillin allergy but also "atypical" organisms resistant to lactams
  • Others: azithromycin and clarithromycin. Broader-spectrum and often more active
• Tetracyclines


  • Four-ring structure with variety of side chains
  • Moderately broad spectrum (most are better at G+ than G-)
  • Bacteriostatic
  • Combine with 30S ribosomal subunit, inhibits binding of aminoacyl-tRNA molecules to the A site of the ribosome
• Tetracycline examples


  • tetracycline, doxycycline, minocycline
  • Treatment: Atypical organisms, inc pneumonias
  • Chlamydia (chest & urogenital / STD)
  • Lyme disease
  • Acne
  • doxycycline - skin and chest G+
  • tigecycline -new variant, broad-spectrum, iv
• Chloramphenicol


  • Broad-spectrum drug with unique nitrobenzene structure
  • Often bacteriostatic
  • Now is chemically synthesized
  • Binds to 23S rRNA on 50S ribosomal subunit and inhibits peptidyl transferase reaction
  • Typhoid fever, brain abscesses, rickettsial and chlamydial infections
  • Toxic with rare but serious side effect so conventionally only used in severe infections
• Lactams


  Others: azithromycin and clarithromycin
• Lactams


  • Broader-spectrum and often more active
• Tetracyclines


  • Four-ring structure with variety of side chains
  • Moderately broad spectrum (most are better at G+ than G-)
  • Bacteriostatic
  • Combine with 30S ribosomal subunit
  • Inhibits binding of aminoacyl-tRNA molecules to the A site of the ribosome
• Tetracycline examples


  • tetracycline, doxycycline, minocycline
• Tetracycline treatment


  • Atypical organisms, inc pneumonias
  • Chlamydia (chest & urogenital / STD)
  • Lyme disease
  • Acne