ORGMED

• Bacteria


  Single-celled microorganisms
• Cell wall properties


  • Gram staining
  • Gram (+)
  • Gram (-)
• Gram (+)


  • Contains peptidoglycan walls
  • Purple (crystal violet, iodine, alcohol, saponin)
• Gram (-)


  • Colorless
  • Simple structure
• Bacteria initiate infection
• Some bacteria are present in the normal flora
• First identified by Anton Van Leeuwenhoek


  1670's
• Anton Van Leeuwenhoek examined a lot to conclude animalcules (tiny living organisms) from teeth scraping and water from ponds
• Louis Pasteur


  • Father of modern microbiology
  • Proposed "germ theory of disease" - microbes can cause specific disease (e.g. anthrax, tuberculosis)
  • Introduced pasteurization
• Joseph Lister


  • Father of Antiseptic Surgery
  • Introduced phenol or carbolic Acid
• Robert Koch


  • Father of Microbial Techniques
  • Father of Medical Microbiology
  • Father of Bacteriology
  • Identified TB, cholera, and typhoid
• Koch's Postulates


  • The microorganism must always be found in similarly diseased animals but not in healthy ones
  • The microorganism must be isolated from a diseased animal and grown in pure culture
  • The isolated microorganism must cause the original disease when inoculated into a susceptible animal
  • The microorganism can be reisolated from the experimentally infected animal
• Paul Ehrlich


  • Father of Chemotherapy
  • Developed Salvarsan, Arsphenamine, C606 to treat syphilis
• Alexander Fleming


  Discovered Penicillin

  
• Bacterial cell and drug targets

  • Inhibition of cell wall synthesis
  • Inhibition of protein synthesis
  • Inhibition of nucleic acid replication and transcription
  • Injury to plasma membrane
  • Inhibition of essential metabolite synthesis
• Inhibitors of cell wall synthesis do not inhibit the cell wall itself, rather they inhibit the synthesis of the cell wall
• Penicillins


  • Most widely effective and least toxic antibacterial drug known
  • Discovered by Alexander Fleming
  • Source: Penicillium chrysogenum, Penicillium notatum
  • Isolated by Florey & Chain
  • Antibiotic that possesses a β-lactam ring and thiazolidine structure

  
• 1. Aminopenicillanic Acid


  • Constitutes the thiazolidine ring or β-lactam
  • Nucleus/core of penicillin
  • Bicyclic system
  • R group side chain varies
• Penicillin mechanism of action

  1. Irreversible acetylation of bacterial cell wall transpeptidase, which carries out cell wall cross-linking

  2. The effectiveness of the β-lactams as bactericidal agents results from the β-lactam ring structurally mimicking the D-alanine-D-alanine portion of the peptidoglycan cell wall with which the transpeptidase normally reacts

  
• Transpeptidase


  • Penicillin binding proteins (cross linker for polymers particularly amino acids)
  • Once bound, ready to cross-link, after which the cell wall is formed
  • No transpeptidase = no cross-link
  • No cross-link = no cell wall
  • No cell wall = bacteriolysis
• Peptidoglycan layer


  • Formed by polymers of NAG (N-acetyl muramic acid) and NAM (N-acetyl glucosamine)
  • NAG binds to NAM, which serves as a precursor for peptidoglycan
  • Polymers make up the cell wall
• Structure-activity relationship of penicillins

  • The strained β-lactam ring is essential
  • The free carboxylic acid is essential
  • The bicyclic system is important
  • The acylamino side chain is essential
  • Sulfur is usual but not essential
  • The stereochemistry of the bicyclic ring with respect to the acylamino side chain is important

  
• Penicillin: can or cannot be given orally
• The acylamino side chain is essential in structure-activity relationships, as it determines whether certain drugs can be given orally
• Types of penicillins


  • Natural penicillins
  • Penicillinase-resistant or antistaphylococcal penicillins
  • Aminopenicillins
  • Extended spectrum/anti-pseudomonal penicillins

  
• Natural penicillins


  Have little modification

  
• Penicillin G


  • Benzylpenicillin
  • Natural
  • Less stable
  • Most widely used
  • Cannot be taken orally (easily broken down by stomach acids)
  • Lacks serious side effects for most patients
  • Active against Gram positive and Gram negative cocci, Gram positive bacilli and spirochetes
  • Used to treat many diseases and infections
  • More active against Gram positive

  
• Penicillin G Procaine


  • First widely used amine salt of Penicillin G
  • Water soluble salt provides rapid development of a plasma concentration of penicillin
  • Insoluble salt prolongs the duration of effect
  • Can be taken orally because most stable
  • Some bacterial infections have no effect, especially to beta-lactamase which can hydrolyze the beta-lactam part of the drug

  
• Penicillin G Benzathine


  • 2 moles of penicillin are available from each molecule
  • Benzylpenicillin
  • Beta-lactamase can hydrolyze the beta-lactam part of penicillin, resulting in inability to bind to transpeptidase

  
• Penicillin V


  • Phenoxymethylpenicillin
  • More acid stable due to the presence of oxygen
  • Can be administered orally
  • Used to treat oral infections

  
• Resistance to penicillin


  • Mutation and genetic transfers
  • Presence of beta-lactamase enzyme (overproduction inhibits drug)
  • High levels of transpeptidase enzyme produced
  • Affinity of the transpeptidase enzyme to penicillin (may be different and unable to bind)
  • Transport back across the outer membrane (efflux)
  • Gram positive: thick peptidoglycan layer produces resistance
  • Gram negative: thin peptidoglycan layer, more penetrable, protein structure (porins)

  
• Beta-lactamase resistant penicillins


  Antistaphylococcal penicillins use a steric shield to block penicillin from accessing the penicillinase or beta-lactamase active site
• Methicillin


  • First effective semi-synthetic penicillin resistant to S. aureus beta-lactamase enzyme
  • Shows poor activity against many other bacterial strains
  • No longer used clinically
  • Adverse effects: kidney failure, interstitial nephritis
  • Largely replaced by oxacillin
  • Toxic metabolites go into renal tubules

  
• Nafcillin


  • Penicillin resistant to beta-lactamase enzymes
  • Contains a naphthalene ring which acts as a steric shield
  • Stable enough in acid

  
• Temocillin


  Has a 6-methoxy group present, similar to the structure of paracetamol
• Isoxazolyl penicillins are another type of beta-lactamase resistant penicillins

  
• Ideal shield


  One large enough to ward off the lactamase enzyme, but sufficiently small to allow the penicillin to bind to the target enzyme
• ANTISTAPHYLOCOCCAL PENICILLINS


  • Methicillin
  • Nafcillin
  • Temocillin
• Methicillin


  • First effective semi-synthetic penicillin with resistance to S. aureus B-lactamase enzyme
  • Shows poor activity against many other bacterial strains
  • No longer used clinically
  • Adverse effects: kidney failure, interstitial nephritis
  • Largely replaced by doxacillin
  • Toxic metabolites go into renal tubules

  
• Nafcillin


  • A penicillin that is resistant to B-lactamase enzymes
  • Contains naphthalene ring which acts as its steric shield
  • Stable enough in acid