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chapter 15 microbial mechanisms of pathogenicity

chapter 15 microbial mechanisms of pathogenicity. pathogenesis. portals of entry & exit. inoculation vs. disease. preferred portal of entry entry DOES NOT EQUAL disease ID 50 : infectious dose for 50% of test population LD 50 : lethal dose for 50% of test population.

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chapter 15 microbial mechanisms of pathogenicity

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  1. chapter 15 microbial mechanisms of pathogenicity

  2. pathogenesis

  3. portals of entry & exit

  4. inoculation vs. disease • preferred portal of entry • entry DOES NOT EQUAL disease • ID50: infectious dose for 50% of test population • LD50 : lethal dose for 50% of test population ID50V. cholerae: 108 cells ID50 inhalation anthrax: <104 spores LD50 botulinum toxin: 0.03 ng/kg 1 mg kills 106 guinea pigs LD50E. coli shiga toxin: 250 ng/kg

  5. pathogenesis: enzymes coagulase & kinase hyaluronidase& collagenase

  6. toxicity: bacterial toxins allow spread and cause damage to the host • toxigenicity: ability to produce a toxin • toxemia: toxin in blood • toxoid: immunization • antitoxin: Ab to toxin

  7. cytotoxins: hemolysins

  8. neurotoxins: Clostridium

  9. Botox therapeutics

  10. enterotoxins: V. cholerae

  11. endotoxins: fever

  12. Salmonella virulence

  13. mechanisms of pathogenicity

  14. chapter 15 learning objectives • Describe pathogenesis from exposure to disease. What factors contribute to disease? • Relate preferred portal of entry and ID50 to the likelihood of infection. • Know how to interpret ID50 and LD50 results. • Describe what is meant by invasiveness and the mechanisms and factors that affect invasiveness (adherence, penetration, avoidance of phagocytosis, ability to cause damage). • Be able to list enzymes produced by microbes than enhance pathogenicity and virulence as well as describe the effects of these enzymes on the host (i.e., hyaluronidase, collangenase, coagulase, kinase). • Differentiate between an endotoxin and an exotoxin as far as source, chemistry and type of molecule (protein, or polysaccharide/lipid). List and understand how examples from class work (e.g., cytotoxin, hemolysin, neurotoxin, enterotoxin, endotoxin). It is not necessary to know the particular details of how each of the three types of exotoxins work.

  15. chapter 20 antimicrobial compounds

  16. chemotherapeutic agents Paul Ehrlich- 1910’s • salvarsan (synthetic arsenic) to treat syphilis Alexander Fleming- 1928 • Penicilliumnotatum Howard Florey- 1940 • P. notatum effectivity

  17. antimicrobials inhibition of protein synthesis: chloramphenicol, erythryomycin, tetracyclines, streptomycin inhibition of cell wall synthesis: penicillins, cephalosporins, bacitracin, vancomycin DNA mRNA Protein Transcription Translation Replication Enzyme inhibition of metabolite synthesis: sulfanimide, trimethoprim inhibition of NA replication & Xscription: quinolones, rifampin injury to plasma membrane: polymyxinB

  18. protein synthesis inhibition Chloramphenicol Binds to 50S portion and inhibits formation of peptide bond 50S portion Protein synthesis site tRNA Messenger RNA 30S portion Direction of ribosome movement Tetracyclines Streptomycin 70S prokaryotic ribosome Changes shape of 30S portion, causing code on mRNA to be read incorrectly Interfere with attachment of tRNA to mRNA–ribosome complex Translation

  19. GFA: metabolite inhibition & synergism

  20. GFAs: nucleic acid inhibition Phosphate Cellular thymidine kinase Incorporated into DNA DNA polymerase Guaninenucleotide Nucleoside Phosphate Viral Thymidine kinase DNA polymerase blocked by false nucleotide. Assembly of DNA stops. False nucleotide(acyclovir triphosphate) Acyclovir (resembles nucleoside)

  21. penicillin & cell wall synthesis inhibition CELL WALL FORMATION autolysins cut wall  new “bricks” inserted  transpeptidase bonds bricks PENICILLIN ACTION transpeptidase binds pen.  forms PBP-antibiotic structure  no new bond formation  cell ruptures cell wall formation, -lactam inhibition longer -lactam video

  22. Abx resistance • outdated, weakened, inappropriateAbx use • use of Abx in animal feed • long-term, low-dose Abx use • aerosolized Abx in hospitals • failure to follow prescribed treatment

  23. the episilometer (E) test- the MIC

  24. Abx resistance • loss of porins- Abx/drug movement into cell • Abx modifying enzymes-cleave β-lactam ring-Anx non-functional • efflux pumps- movement out of cell • target site mutations-enzymes-polymerases-ribosomes-LPS layer Abx resistance mechanism of action

  25. the effect of -lactamase on -lactam Abx VERY STABLE RESISTANCE • NDM-1 (metallo- -lactamase) • K. pneumoniae & E. coli, plasmids & chromosomal • KPC (K. pneumoniae carbapenemase, class of -lactamase) RESISTANCE RESISTED • clavulinic acid/sulbactam bind -lactamase • can be hydrolyzed by high copy # plasmid -lactamase

  26. Narrow-spectrum β-lactamase sensitive benzathine penicillin benzylpenicillin (penicillin G) phenoxymethylpenicillin (penicillin V) procaine penicillin Penicillinase-resistant penicillins methicillin, oxacillin nafcillin, cloxacillin dicloxacillin, flucloxacillin β-lactamase-resistant penicillins temocillin Moderate-spectrum amoxicillin, ampicillin Broad-spectrum co-amoxiclav (amoxicillin+clavulanic acid) Extended-spectrum azlocillin, carbenicillin ticarcillin, mezlocillin, piperacillin Cephalosporins 1st generation: moderate cephalexin, cephalothin cefazolin 2nd generation: moderate, anti-Haemophilus cefaclor, cefuroxime, cefamandole 2nd generation cephamycins: moderate, anti-anaerobe cefotetan, cefoxitin 3rd generation: broad spectrum ceftriaxone, cefotaxime cefpodoxime, cefixime ceftazidime (anti-Pseudomonas activity) 4th generation: broad, anti-G+ & β-lactamase stability cefepime, cefpirome Carbapenems and Penems: broadest spectrum imipenem (with cilastatin), meropenem ertapenem, faropenem, doripenem Monobactams aztreonam (Azactam), tigemonam nocardicin A, tabtoxinine-β-lactam -lactams

  27. 2009 CASE STUDY, U. of Pittsburgh Medical Center 6/2008- post-surgical hospitalization, septicemia (E. coli & E. cloacae) 7/2008- UTI, E. coli & P. mirabilis 8/2008- UTI, E. coli (imipenem S) & K. pneumoniae (imipenem R & ertapenem R) 9/2008- abdominal tissue infection, E. coli & K. pneumoniae (both R to Abx) 11/2008- sputum P. aeruginosa & S. marcescens, K. pneumoniae 12/2008- MDR-pneumonia, A. baumanii & M. morganii 1/2009- sputum, S. marcescens (ertapenem & imipenem R) bacterial resistance

  28. chapter 20learning objectives • What is the major difference between an antibiotic and a drug? What were the first drug and antibiotic? • Antimicrobial agents target which areas of the bacterial cell? How specifically do antibiotics inhibit protein synthesis? • Describe the mechanism of action of penicillin on the bacterial cell. • List and explain the effects of antibiotic/drug action on the bacterial cell and the action of penicillin specifically. • Discuss the mode of action of growth factor analogs in general and sulfa drugs and acyclovir specifically. • How are antibiotic use and antibiotic resistance related? How are antibiotics abused? • Define bacteriolytic, bacteriostatic, bactericidal, MIC, MBC. Describe how MIC is calculated and what it will tell you about a given bacterium. • Understand the four major ways that antibiotic resistance is achieved. Include -lactamases and clavulanate/clavulinic acid specifically.

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