chapter 15 microbial mechanisms of pathogenicity

Transcription

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 entry into preferred portal of entry DOES NOT EQUAL disease ID 50 : infectious dose for 50% of population inhalation anthrax: <10 4 spores V. cholerae: 10 8 cells LD 50 : lethal dose for 50% botulinum toxin: 0.03 ng/kg E. coli shiga toxin: 250 ng/kg

5 pathogenesis: enzymes hyaluronidase & collagenase coagulase & kinase leukocidins

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 exotoxin endotoxin source Gram positive/enterics Gram negative expressed gene chemical make-up protein lipid neutralized by antitoxin? yes fever? no yes LD 50 (relative) small large outer membrane component no

7 cytotoxins: hemolysins

8 neurotoxins: Clostridium

9 enterotoxins: V. cholerae

10 endotoxins: fever

11 Salmonella virulence

12 mechanisms of pathogenicity Inactivating host defenses

13 chapter 15 learning objectives 1. Describe pathogenesis from exposure to disease. What factors contribute to disease? 2. Relate preferred portal of entry and ID50 to the likelihood of infection. 3. Know how to interpret ID50 and LD50 results. 4. Describe what is meant by invasiveness and the mechanisms and factors that affect invasiveness (adherence, penetration, avoidance of phagocytosis, ability to cause damage). 5. 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). 6. 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.

14 chapter 20 antimicrobial compounds

15 chemotherapeutic agents Paul Ehrlich s salvarsan (synthetic arsenic) to treat syphilis Alexander Fleming Penicillium notatum Howard Florey P. notatum effectivity

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

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

18 GFA: metabolite inhibition & synergism

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

20 cell wall synthesis CELL WALL FORMATION autolysins cut wall new bricks inserted transpeptidase/pbp bonds bricks

21 penicillin & cell wall synthesis inhibition PENICILLIN ACTION transpeptidase/pbp binds pen. PBP-antibiotic structure formed no new bond formation cell ruptures

22 Abx resistance 1. outdated, weakened, inappropriate Abx use 2. use of Abx in animal feed 3. long-term, low-dose Abx use 4. aerosolized Abx in hospitals 5. failure to follow prescribed treatment

23 the episilometer (E) test- the MIC

24 1. loss of porins Abx resistance - Abx/drug movement into cell 2. Abx modifying enzymes -cleave β-lactam ring -Anx non-functional 3. efflux pumps - movement out of cell 4. target site mutations -enzymes -polymerases -ribosomes -LPS layer Resistance mechanisms

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 -lactams Cephalosporins 1 st generation: moderate cephalexin, cephalothin cefazolin 2 nd generation: moderate, anti-haemophilus cefaclor, cefuroxime, cefamandole 2 nd generation cephamycins: moderate, antianaerobe cefotetan, cefoxitin 3 rd generation: broad spectrum ceftriaxone, cefotaxime cefpodoxime, cefixime ceftazidime (anti-pseudomonas activity) 4 th 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

27 bacterial resistance 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)

28 chapter 20learning objectives 1. What is the major difference between an antibiotic and a drug? What were the first drug and antibiotic? 2. Antimicrobial agents target which areas of the bacterial cell? How specifically do antibiotics inhibit protein synthesis? 3. Describe the mechanism of action of penicillin on the bacterial cell. 4. List and explain the effects of antibiotic/drug action on the bacterial cell and the action of penicillin specifically. 5. Discuss the mode of action of growth factor analogs in general and sulfa drugs and acyclovir specifically. 6. How are antibiotic use and antibiotic resistance related? How are antibiotics abused? 7. Define bacteriolytic, bacteriostatic, bactericidal, MIC, MBC. Describe how MIC is calculated and what it will tell you about a given bacterium. 8. Understand the four major ways that antibiotic resistance is achieved. Include -lactamases and clavulanate/clavulinic acid specifically.