chapter 4

• an important quality for an antimicrobial drug is selective toxicity
• selective toxicity is when it selectively kills or inhibits the growth of microbial targets while causing minimal or no harm to the host
• most drugs are in clinical use because the prokaryotic cell provides a greater variety of unique targets for selective toxicity, in comparison to fungi, parasites and viruses
• cell wall

  • b lactams (penicillins, cephalosphorins, monobactams, carbapenems)
  • glycopeptides (vancomycin)
  • bacitracin
• DNA synthesis

  • fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin)
• RNA synthesis

  • rifamycins (rifampin)
• Plasma membrane

  • polymyxins (polymyxin B, colistin)
  • lipopeptide (Daptomycin)
• ribosomes

  • 30s subunit (Aminoglycosides, tetracyclines)
  • 50s subunit (macrolides, lincosamides, chloramphenicol, oxazolidinones)
• metabolic pathways

  • folic acid synthesis (sulfonamides, sulfones, trimethoprim)
  • mycolic acid synthesis (izoniazid)
• mycobacterial ATP synthase inhibitor (Diarylquinoline)
• antibacterial cells that target cell wall biosynthesis are bactericidal in action
• penicillin is one of several antibacterials within class b lactams. it includes penicillin, cephalosporins, monobactams, and carbapenems. characterize by the presence of b lactam ring
• b lactam ring block the crosslinking of peptide chains during the biosynthesis of new peptidoglycan in the bacterial cell wall. b lectam is similar to the structure of the peptidoglycan subunit that is recognizdd by crosslinking transpeptidase enzyme / PBP (penicillin binding protein)

  A) O
• strategic chemical changes to the R group have allowed for development of a wide variety of semisynthetic b lactam drugs, with increased potency, expanded spectrum of activity and longer half lives for better dosing
• penicillin G and penicllin V are natural antibotics from fungi. and are active against gram positive and a few fram negative such as pasteurella multocida
• • amino group (NH2) + penicillin G - aminopenicillin (ampicillin and amoxicillin) -- increase spectrum against more gram nega pathogen
  • addition of OH to amoxicillin increased acid stability, which allows for improved oral absorption
  • methicillin is a semisynthetic penicillin developed to address spread off enzyme (penicillinases) that were inactivating the other penicillins
  • changing r group of penicillin G to more bulky dimethoxyphenyl group provided protection of the b lactam ring from enzymatic destruction by penicillinases, giving us the first penicillinase resistant penicllin
• cephalosporins contain a b lactam ring and block the transpeptidase activit of pbp. however, the b lactam ring of cephalosporins is fused to a six membered ring rather than 5 like in penicillins. this chemical difference provides cephalosporins with an increased resistance to enzymatic inactivation by b lactamases
• cephalosporin c was originally isolated from the fungus cephalosporium acremonium in the 1950s and has a similar spectrum of activity to that of penicillin against gram positive bacteria but is active against more gram nega than penicillin
• cephalosporin c has 2 r groups compared with just one r group for penicillin and it provides diversity
• family of cephalosporin is much larger than the penicillins and these drugs have been classified into generation based on their spectrum of activity. increasing in spectrum from narrow first gen to broad fourth gen. a 5th gen have is active against methicillin resistant staphylococcus aureus
• carbapenems and monobactams also have b lactam ring as part of their co structure, and they inhibit the transpeptidase activity of pbp. the only monobactam used clinically is aztreonam. a narrow spectrum antibacterial with activity against gram nega bacteria. in contrast carbapenem family like imipenem, meropenem and doripenem provide very broad spectrum activity against gram posi and gram nega bacteria pathogens
• Vancomycin


  Creates a structural blockage which prevents the cell wall subunits from being incorporated into growing N-acetylglucosamine and N-acetylmuramic acid (NAM-NAG) backbone of the peptidoglycan structure (transglycosylation)
• Vancomycin


  A very large complex molecule that inhibits cell wall and is bactericidal
• Vancomycin


  Structurally blocks transpeptidation
• Actinomycete amycolatopsis orientalis

  The bacteria from which vancomycin is derived
• Glycopeptides


  A family of drugs that includes vancomycin
• The drug vancomycin from glycopeptides family was discovered in the 1950s as a natural antibiotic from actinomycete amycolatopsis orientalis
• Vancomycin

  • Bactericidal against gram positive but not active under gram negative due to its inability to penetrate under protective outer membrane
• bacitracin consist of group of structurally similar peptide antibiotics originally isolated from bacillus subtilis
• bacitracin blocks the activity of a specific cell membrane molecule responsible for the movement of peptidoglycan precursors from the cytoplasm to the exterior of the cell, preventing their incorporation into th cell wall
• bacitracin is effective against a wide range of bacteria, including gram posi on skin like staphylococcus and streptococcus. although it may be administered orally or intramuscularly, bacitracin is nephrotoxic (kidney damaging) therefore it is combined with neomycin and polymyxin in topical ointments such as neosporin
• antibacterials block steps in the biosynthesis of peptidoglycan, making cells more susceptible to osmotic lysis. therefore, atnibacterials that target cell wall biosynthesis are bactericidal. selective toxic as well
• ..

  A) penicillin G

  B) penicillin V

  C) ampicillin V

  D) amoxicillin

  E) methicillin

  F) G+ and a few G-

  G) similar to penicillin G

  H) G+ and more G- than penicillin

  I) similar to ampicillin

  J) g+ only including b lactamase producers

  K) parenteral

  L) oral

  M) parenteral and oral

  N) oral (better than ampicillin

  O) parenteral

  
• ..

  A) interact daily with PBPs and inhibit transpeptidase act

  B) penicillin G and penicillin V

  C) narrow spectrum against gram positive and a few gram -

  D) natural

  
• ..

  A) ampicillin, amoxicillin

  B) semisynthetic

  C) narrow spectrum against gram + but increased gram -

  D) methicillin

  E) semisynthetic

  F) narrow spectrum against gram +, & strains w/penicillase

  
• ..

  A) cephalosphorin c

  B) natural

  C) narrow spec like penicillin but with increased gram -

  D) first generation cephalosphorin

  E) semisynthetic

  F) narrow spectrum similar to cephalosphorin c

  G) second - generation cephalosphorins

  H) semisynthetic

  I) narrow spec but with increased gram - compared to 1st g

  J) third and fourth generation cephalosphorins

  K) semisynthetic

  L) broad spectrum, including b lactamase producers

  M) 5th gen cephalosphorins

  N) semisynthetic

  O) broad spectrum including MRSA

  
• ..

  A) aztreonam

  B) semisynthetic

  C) narrow spec gram - including b lactamase producer

  D) imipenem, meropenem, doripenem

  E) semisynthetic

  F) broadest spectrum against b lactamase producers

  G) vancomycin

  H) natural

  I) bind to peptide chain of peptidoglycan

  J) narrow spec against multidrug resistant strains

  
• ..

  A) bacitracin

  B) natural

  C) blocks transport across cytoplasmic membrane

  D) broad spectrum

  
• ..

  A) inhibit cell wall synthesis

  B) penicillin binding proteins

  C) peptidoglycan subunits

  D) peptidoglycan subunit transport

  E) 30 s ribosomal subunit

  F) 50 s ribosomal subunit

  G) lipopolsacharide, inner and outer membranes

  H) rna

  I) dna

  J) inhibit biosynthesis of proteins

  K) disrupt membranes

  L) inhibit nucleic acid synthesis

  M) antimetabolite

  N) folic acid synthesis enzymes

  O) mycolic acid synthesis enzyme

  P) mycobacterial atp synthase inhibitor

  Q) mycobacterial atp synthase

  
• ..

  A) penicillin

  B) cephalosphorin

  C) monobactam

  D) carbapenem