Antimicrobial chemotherapy and Drug resistance

What did Sir Alexander Fleming discover?

bacteriolytic substance, the lysozyme

What else did Fleming discover?

found a halo of inhibition of Staphylococcus around a mold contaminant; penecillin

Who was penicillin originally discovered by and who accidentally discovered it?

-Ernest Duchesne
-Alexander Fleming

What did Florey, Chain, and Heatley do?

demonstrated the effectiveness of penicillin

What is the toxicity of antimicrobial drugs?

selective toxicity

What is selective toxicity?

ability of drug to kill or inhibit pathogen while damaging host as little as possible

What is the therapeutic dose?

drug level required for clinical treatment

What is the toxic dose?

drug level at which drug becomes too toxic for patient (produces side effects)

What is the therapeutic index?

ratio of toxic dose to therapeutic dose

What are side effects?

undesirable effects of drugs on host cells

What are narrow-spectrum drugs?

attack only a few different pathogens

What are broad-spectrum drugs?

attack many different pathogens

What are cidal agents?

kill microbes

What are static agents?

inhibits growth of microbes

What is the minimal inhibitory concentration (MIC)?

the lowest concentration of a drug that prevents growth of a particular organism

What is the minimum lethal concentration?

the lowest concentration of a drug that kills the pathogen

How can we determine the level of antimicrobial activity?

-dilution susceptibility test
-Kirby Bauer method
-E test

What happens in a dilution susceptibility test? What is used in it?

-drug is diluted in regular intervals (normally 2x)
-Mueller-Hinton broth is normally used

How does the Kirby-Bauer method work?

-fresh bacteria are inoculated on a Mueller-Hinton plate
-dried for 5 minutes and disks with antibiotic are added

What is the E test convenient for use with?

anaerobic pathogens

What is the E test similar to?

disk diffusion method, but uses strip rather than disk

E test strips contain a _______ of an antibiotic

gradient

How can we indicate MIC in E test?

intersection of elliptical zone of inhibition with strip

Do antibiotics all target the same thing?

no, there is a wide variety of what the target is

What is the main class of antibiotics?

beta lactams that target the cell wall

What are 3 groups of antibiotics that inhibit cell wall synthesis?

-penicillins
-cephalosporins
-vancomycin

Penicillin is a derivative of what acid?

6-aminopenicillanic aicd

Where can the chemical modifications occur?

NH2

How do penicillins inhibit cell wall synthesis?

inhibits transpeptidation (crosslinking), leading to an unstable cell wall

Penicillin has what main structure?

beta lactam ring

Pencillin binding proteins recognize what sequence?

D-ala D-ala and beta lactam

How can some bacteria be beta-lactam resistance?

have beta lactam antibiotics called beta lactamases

How do beta lactamases work?

cleave open the ring of penicillin

What is clavulanic acid?

beta lactamase inhibitor

Clavulanic acid is marketed with amoxicillin as _______

Augmentin

What does the structure of clavulanic acid resemble and why is this important?

mimic penicillin, and the beta lactamases cleave this instead of penecillim

What are cephalosporins originally isolated from?

fungus, cephalosporium

What structure do cepahlosporins contain?

beta lactam ring

Cephalosporins contain ____ broad generations

4

What is worth mentioning about each generation?

1: mainly gram +
2: improved against gram -
3: passes BBB
4: good with both gram + and -

Vacomycin is a ________ antibiotic

glycopeptide

Vancomycin is produced by what?

produced by Streptomyces orientalis

Where does vancomycin bind? What does it inhibit?

-D ala D ala
-inhibits transpeptidation

Would we use penecillin or vancomycin first?

penecillin

How can vancomycin resistance occur?

lactate bind to D ala D ala, and vancomycin can not bind to it

What are 3 groups of antibiotics that inhibit protein synthesis?

-aminoglycosides
-tetracyclines
-macrolides

What is a common thread of all the different aminoglycosides?

all contain cyclohexane ring and amino sugars

Most aminoglycosides are synthesized by what?

different species of Steptomyces

Where do aminoglycosides bind?

30S ribosomal subunit

What are the 3 common resistance mechanisms of aminoglycosides?

-acetylation of an amino group
-ATP dependent adenylation of a hydroxyl group
-ATP dependent phosphorylation of a hydroxyl group

What is common among tetracyclines?

common 4 ring structure

What are tetracycliens similar to? Where do they bind?

-aminoglycosides
-bind the 30S subunit

What are 3 mechanisms of tetracyclines resistance?

-efflux
-ribosomal modification
-drug modification

What is a commonality of macrolides?

12-22 carbon lactone rings linked by 1 or more sugars

Where does Erythromycin bind?

the 23S rRNA of the 50S subunit

What are 2 groups of antibiotics that are metabolic inhibitors?

sulfonamides and trimethoprim

What is sulfanilamide and analog of?

p-aminobenzoic acid (PABA)

Why is folic acid essential?

purine synthesis

What do metabolic inhibitors do?

inhibit synthesis of folic acid

Sulfonamides inhibit what enzyme?

dihydropteroate synthase

Trimethoprim is an analog of what?

dihydrofolic acid

Trimethoprim inhibits what enzyme?

dihydrofolate reductase

What is an antibiotic example of nucleic acid synthesis inhibitors?

Quinolones

What do quinolones inhibit?

DNA gyrase and topoisomerase IV