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  1. 1. Maria Ellery Mendez, MD, DPASMAP,FPAMS,FPAAAM Department of Microbiology Our Lady of Fatima University
  2. 2. ANTIMICROBIAL AGENT • any chemical or drug used to treat an infectious disease, either by inhibiting or killing the pathogens in vivo
  3. 3. ANTIMICROBIAL AGENT Ideal Qualities: 1. kill or inhibit the growth of pathogens 2. cause no damage to the host 3. cause no allergic reaction to the host 4. stable when stored in solid or liquid form 5. remain in specific tissues in the body long enough to be effective 6. kill the pathogens before they mutate and become resistant to it
  4. 4. ANTIBIOTICS  Substances derived from a microorganism or produced synthetically, that destroys or limits the growth of a living organism
  5. 5. ANTIBIOTICS – Sources 1. Natural a.Fungi – penicillin, griseofulvin b.Bacteria – Bacillus sp. (polymixin, bacitracin) ; Actinomycetes (tetracycline, chloramphenicol, streptomycin) 2. Synthetic
  6. 6. ANTIBIOTICS – Classification I. Accdg to antimicrobial activity 1. Bactericidal 2. Bacteriostatic I. Accdg to bacterial spectrum of activity 1. Narrow spectrum 2. Broad spectrum
  7. 7. ANTIBIOTICS – Classification III.Accdg to absorbability from the site of administration to attain significant concentration for the treatment of systemic infection 1. Locally acting 2. Systemic
  8. 8. ANTIBIOTICS – Classification IV.Accdg to mechanism of action 1. Inhibit bacterial cell wall synthesis 2. Alter the function and permeability of the cell membrane 3. Inhibit protein synthesis (translation and transcription) 4. Inhibit nucleic acid synthesis
  9. 9. Inhibition of cell wall synthesis Target: block peptidoglycan (murein) synthesis Peptidoglycan  Polysaccharide (repeating disaccharides of N- acetylglucosamine and N-acetylmuramic acid) + cross-linked pentapeptide  Pentapeptide with terminal D-alanyl-D-alanine unit  required for cross-linking  Peptide cross-link formed between the free amine of the amino acid in the 3rd position of the peptide & the D-alanine in the 4th position of another chain
  10. 10. Inhibition of cell wall synthesis Α. β-lactam antibiotics  inhibit transpeptidation reaction (3rd stage) to block peptidoglycan synthesis  involves loss of a D-alanine from the pentapeptide  Steps: a. binding of drug to PBPs b. activation of autolytic enzymes (murein hydrolases) in the cell wall c. degradation of peptidoglycan d. lysis of bacterial cell
  11. 11. Inhibition of cell wall synthesis Α. β-lactam antibiotics Penicillin binding proteins (PBPs)  enzymes responsible for: a. cross-linking (transpeptidase) b. elongation (carboxypeptidase) c. autolysis
  12. 12. Inhibition of cell wall synthesis Α. β-lactam antibiotics Lysis of bacterial cell o Isotonic environment  cell swelling  rupture of bacterial cell o Hypertonic environment – microbes change to protoplasts (gram +) or spheroplasts (gram -) covered by cell membrane  swell and rupture if placed in isotonic environment
  13. 13. Inhibition of cell wall synthesis Α. β-lactam antibiotics o intact ring structure essential for antibacterial activity o inhibition of transpeptidation enzyme due to structural similarity of drugs (penicillin and cephalosporin) to acyl-D-alanyl-D- alanine
  14. 14. Inhibition of cell wall synthesis Α. β-lactam antibiotics PENICILLIN  Source: Penicillium spp (molds)  inhibit final cross-linking step  bind to active site of the transpeptidase & inhibit its activity  bactericidal but kills only when bacteria are actively growing  inactivated by β-lactamases
  15. 15. Inhibition of cell wall synthesis Α. β-lactam antibiotics CEPHALOSPORINS  similar structure and mechanism of action as penicillin  most are products of molds of the genus Cephalosporium
  16. 16. Inhibition of cell wall synthesis B. Other β-lactam antibiotics CARBAPENEMS  structurally different from penicillin and cephalosporin  Imipenem  with widest spectrum of activity of the β-lactam drugs  Bactericidal vs. many gram (+), gram (-) and anaerobic bacteria  not inactivated by β-lactamases
  17. 17. Inhibition of cell wall synthesis A. Other β-lactam antibiotics MONOBACTAMS (Aztreonam)  activity vs. gram negative rods  useful in patients hypersensitive to penicillin
  18. 18. Inhibition of cell wall synthesis C. Other Cell Wall Inhibitors  Inhibit precursor for bacterial cell wall synthesis VANCOMYCIN  Source: Streptomyces orientalis  Inhibit 2nd stage of peptidoglycan synthesis by: a. binding directly to D-alanyl-D-alanine  block transpeptidase binding b. inhibiting bacterial transglycosylase  S. aureus & S. epidermidis infection resistant to penicillinase-resistant PEN
  19. 19. Inhibition of cell wall synthesis C. Other Cell Wall Inhibitors CYCLOSERINE  Inhibit 2 enzymes  D-alanine-D-alanine synthetase and alanine racemase  catalyze cell wall synthesis  inhibit 1st stage of peptidoglycan synthesis  structural analogue of D-alanine  inhibit synthesis of D-alanyl-D-alanine dipeptide  second line drug in the treatment of TB
  20. 20. Inhibition of cell wall synthesis C. Other Cell Wall Inhibitors ISONIAZID & ETHIONAMIDE  Isonicotinic acid hydrazine (INH)  Inhibit mycolic acid synthesis ETHAMBUTOL  Interferes with synthesis of arabinogalactan in the cell wall
  21. 21. Inhibition of cell wall synthesis C. Other Cell Wall Inhibitors BACITRACIN  Source: Bacillus licheniformis  Prevent dephosphorylation of the phospholipid that carries the peptidoglycan subunit across the membrane  block regeneration of the lipid carrier & inhibit cell wall synthesis  Too toxic for systemic use  treatment of superficial skin infections
  22. 22. Inhibition of cell membrane function A. POLYMYXINS  Source: Bacillus polymyxa  With positively charged free amino group  act like a cationic detergent  interact with lipopolysaccharides & phospholipid in outer membrane  increased cell permeability  Activity: gram negative rods, especially Pseudomonas aeruginosa
  23. 23. Inhibition of cell membrane function B. POLYENES (Anti-fungal)  Require binding to a sterol (ergosterol)  change permeability of fungal cell membrane AMPHOTERICIN B  Preferentially binds to ergosterol  With series of 7 unsaturated double bonds in macrolide ring structure  Activity: disseminated mycoses
  24. 24. Inhibition of cell membrane function B. POLYENES (Anti-fungal) NYSTATIN  Structural analogue of amphotericin B  Topical vs. Candida C. AZOLES (Anti-fungal)  Block cytP450-dependent demethylation of lanosterol  inhibit ergosterol synthesis  Ketoconazole, Fluconazole, Itraconazole, Miconazole, Clotrimazole
  25. 25. Inhibition of protein synthesis  Binds the ribosomes  result in: 1. Failure to initiate protein synthesis 2. No elongation of protein 3. Misreading of tRNA-deformed protein
  26. 26. Inhibition of protein synthesis A. Drugs that act on the 30S subunit AMINOGLYCOSIDES (Streptomycin)  Mechanism of bacterial killing involves the ff. steps: 1. Attachment to a specific receptor protein (e.g. P 12 for Streptomycin) 2. Blockage of activity of initiation complex of peptide formation (mRNA + formylmethionine + tRNA) 3. Misreading of mRNA on recognition region  wrong amino acid inserted into the peptide
  27. 27. Inhibition of protein synthesis A. Drugs that act on the 30S subunit TETRACYCLINES  Source: Streptomyces rimosus  Bacteriostatic vs. gram (+) and gram (-) bacteria, mycoplasmas, Chlamydiae & Rickettsiae  Block the aminoacyl transfer RNA from entering the acceptor site  prevent introduction of new amino acid to nascent peptide chain
  28. 28. Inhibition of protein synthesis A. Drugs that act on the 30S subunit OXAZOLIDINONES (LINEZOLID)  interfere with formation of initiation complex  block initiation of protein synthesis  Activity: Vancomycin-resistant Enterococci, Methicillin-resistant S. aureus (MRSA) & S. epidermidis and Penicillin-resistant Pneumococci
  29. 29. Inhibition of protein synthesis B. Drugs that act on the 50S subunit CHLORAMPHENICOL  Inhibit peptidyltransferase  prevent synthesis of new peptide bonds  Mainly bacteriostatic; DOC for treatment of typhoid fever
  30. 30. Inhibition of protein synthesis B. Drugs that act on the 50S subunit MACROLIDES (Erythromycin, Azithromycin & Clarithromycin)  Binding site: 23S rRNA  Mechanism: 1. Interfere with formation of initiation complexes for peptide chain synthesis 2. Interfere with aminoacyl translocation reactions  prevent release of uncharged tRNA from donor site after peptide bond is formed (Erytnromycin)
  31. 31. Inhibition of protein synthesis B. Drugs that act on the 50S subunit LINCOSAMIDES (Clindamycin)  Source: Streptomyces lincolnensis  resembles macrolides in binding site, anti- bacterial activity and mode of action  Bacteriostatic vs. anaerobes, gram + bacteria (C. perfringens) and gram – bacteria (Bacteroides fragilis)
  32. 32. Inhibition of protein synthesis C. Drugs that act on both the 30S and 50S subunit GENTAMICIN, TOBRAMYCIN, NETILMICIN  Treatment of systemic infections by susceptible gram (-) bacteria including Enterobacteriaceae & Pseudomonas AMIKACIN  Treatment of infection by gram (-) bacteria resistant to other aminoglycosides KANAMYCIN  Broad activity vs. gram (-) bacteria except Pseudomonas
  33. 33. Inhibition of nucleic acid synthesis A. Inhibition of precursor synthesis  Inhibit synthesis of essential metabolites for synthesis of nucleic acid SULFONAMIDES  Structure analogue of PABA (precursor of tetrahydrofolate)  inhibit tetrahydrofolate  methyl donor in synthesis of A, G and T  Bacteriostatic vs. bacterial diseases (UTI, otitis media 20 to S. pneumoniae or H. influenzae, Shigellosis, etc.)  DOC for Toxoplasmosis & Pneumocystis pneumonia
  34. 34. Inhibition of nucleic acid synthesis A. Inhibition of precursor synthesis TRIMETHOPRIM  Inhibit dihydrofolate reductase (reduce dihydrofolic to tetrahydrofolic acid)  inhibit purine synthesis TRIMETHOPRIM + SULFAMETHOXAZOLE  Produce sequential blocking  marked synergism of activity  Bacterial mutants resistant to one drug will be inhibited by the other
  35. 35. Inhibition of nucleic acid synthesis B. Inhibition of DNA synthesis QUINOLONES  Inhibit α subunit of DNA gyrase  (+) supercoiling  (-) DNA synthesis  Bactericidal; not recommended for children & pregnant women since damages growing cartilage  Fluoroquinolones (Ciprofloxacin), Norfloxacin, Ofloxacin, etc.
  36. 36. Inhibition of nucleic acid synthesis B. Inhibition of DNA synthesis NOVOBIOCIN  Inhibit β subunit of DNA gyrase FLUCYTOSINE (Anti-fungal)  Nucleoside analogue  inhibit thymidylate synthetase  limit supply of thymidine
  37. 37. Inhibition of nucleic acid synthesis B. Inhibition of DNA synthesis METRONIDAZOLE  Anti-protozoal; anaerobic infections  Antimicrobial property due to reduction of its nitro group by bacterial nitroreductase  (+) production of cytotoxic compounds  disrupt host DNA
  38. 38. Inhibition of nucleic acid synthesis C. Inhibit RNA synthesis RIFAMPICIN  Semisynthetic derivative of rifamycin B (produced by Streptomyces mediterranei)  Binds to DNA-dependent RNA polymerase  block initiation of bacterial RNA synthesis  Bactericidal vs. M. tuberculosis and aerobic gram (+) cocci
  39. 39. RESISTANCE ACQUISITION OF BACTERIAL RESISTANCE INTRINSIC RESISTANCE  Stable genetic property encoded in the chromosome and shared by all strains of the species  Usually related to structural features (e.g. permeability of the cell wall)  e.g. Pseudomonas cell wall limits penetration of antibiotics
  40. 40. RESISTANCE ACQUISITION OF BACTERIAL RESISTANCE ACQUIRED RESISTANCE  Species develop ability to resist an antimicrobial drug to which it is as a whole naturally susceptible  Two mechanisms: 1. Mutational – chromosomal 2. Genetic exchange – transformation, transduction, conjugation
  41. 41. RESISTANCE INTRINSIC RESISTANCE – EXAMPLES: 1. Mutation affecting specific binding protein of the 30S subunit  Streptomycin-resistant M. tuberculosis & S. faecalis 2. Mutation in porin proteins  impaired antibiotic transport into the cell  lead to multiple resistance  P. aeruginosa 3. Mutation in PBPs  Strep pneumoniae 4. Altered DNA gyrase  quinolone-resistant E. coli
  42. 42. RESISTANCE ACQUIRED RESISTANCE – EXAMPLES: 1. Resistance (R) plasmids  Transmitted by conjugation 2. mecA gene  Codes for a PBP with low affinity for β- lactam antibiotics  Methicillin-resistant S. aureus
  43. 43. RESISTANCE ORIGIN OF DRUG RESISTANCE NON-GENETIC 1. Metabolically inactive organisms may be phenotypically resistant to drugs – M. tuberculosis 2. Loss of specific target structure for a drug for several generations 3. Organism infects host at sites where antimicrobials are excluded or are not active – aminoglycosides (e.g. Gentamicin) vs. Salmonella enteric fevers (intracellular)
  44. 44. RESISTANCE GENETIC 1. Chromosomal  Occurs at a frequency of 10-12 to 10-7  20 to spontaneous mutation in a locus that controls susceptibility to a given drug  due to mutation in gene that codes for either: a. drug target b. transport system in the membrane that controls drug uptake
  45. 45. RESISTANCE GENETIC 2. Extrachromosomal a. Plasmid-mediated  Occurs in many different species, esp. gram (-) rods  Mediate resistance to multiple drugs  Can replicate independently of bacterial chromosome  many copies  Can be transferred not only to cells of the same species but also to other species and genera
  46. 46. RESISTANCE MECHANISMS THAT MEDIATE BACTERIAL RESISTANCE TO DRUGS 1. Production of enzymes that inactivate the drug α. β-lactamase  S. aureus, Enterobacteriaceae, Pseudomonas, H. influenzae a. Chloramphenicol acetyltransferase  S. aureus, Enterobacteriaceae a. Adenylating, phosphorylating or acetylating enzymes (aminoglycosides)  S. aureus, Strep, Enterobacteriaceae, Pseudomonas
  47. 47. RESISTANCE MECHANISMS THAT MEDIATE BACTERIAL RESISTANCE TO DRUGS 2. Altered permeability to the drug  result to decreased effective intracellular concentration  Tetracycline, Penicillin, Polymixins, Aminoglycosides, Sulfonamides
  48. 48. RESISTANCE MECHANISMS THAT MEDIATE BACTERIAL RESISTANCE TO DRUGS 3. Synthesis of altered structural targets for the drug a. Streptomycin resistance – mutant protein in 30S ribosomal subunit  delete binding site  Enterobacteriaceae b. Erythromycin resistance – altered receptor on 50S subunit due to methylation of a 23S rRNA  S. aureus
  49. 49. RESISTANCE MECHANISMS THAT MEDIATE BACTERIAL RESISTANCE TO DRUGS 4. Altered metabolic pathway that bypasses the reaction inhibited by the drug Sulfonamide resistance – utilize preformed folic acid instead of extracellular PABA  S. aureus, Enterobacteriaceae
  50. 50. RESISTANCE MECHANISMS THAT MEDIATE BACTERIAL RESISTANCE TO DRUGS 5. Multi-drug resistance pump  Bacteria actively export substances including drugs in exchange for protons  Quinolone resistance
  51. 51. RESISTANCE LIMITATION OF DRUG RESISTANCE 1. Maintain sufficiently high levels of the drug in the tissues  inhibit original population and first-step mutants. 2. Simultaneous administration of two drugs that do not give cross-resistance  delay emergence of mutants resistant to the drug (e.g. INH + Rifampicin) 3. Limit the use of a valuable drug  avoid exposure of the organism to the drug
  52. 52. THE END