antimicrobial resistance

who developed the concept of selective toxicity?

Paul Ehrlich

who worked with Ehrlich to identify arsenic compounds that effectively treated syphillis?

Sahachiro Hato

who discovered sulfonamides/sulfa drugs?

Gerhard Domagk, Jacques & Therese Trefouel

who first discovered penicillin?

Ernest Duchesne

who rediscovered penicillin?

Alexander Fleming

who demonstrated the effectiveness of penicillin?

Florey, Chain, & Heatley

who received the nobel prize in 1945 for the discovery & production of penicillin?

Fleming, Florey, & Chain

who discovered streptomycin?

Selman Waksman

who was awarded the nobel prize in 1952 for the discovery of streptomycin?

Salman Waksman

streptomycin

antibiotic active against tuberculosis

general characteristics of antimicrobial drugs

selective toxicity, therapeutic dose, toxic dose, therapeutic index, side effects

selective toxicity

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

therapeutic dose

drug level required for treatment of an infection

toxic dose

drug level at which the drug becomes too toxic for the patient & produces side effects

therapeutic index

ratio of toxic dose to therapeutic dose

side effects

undesirable effects of drugs on host cells

narrow-spectrum drugs

attack only a few different pathogens

broad-spectrum drugs

attack many different kinds of bacteria

cidal agent

kills the target pathogen

static agent

reversibly inhibits growth of microbes

2 ways of expressing effectiveness of antimicrobial drugs

minimal inhibitory concentration & minimal lethal concentration

what does MIC stand for?

minimal inhibitory concentration

MIC

lowest concentration of drug that prevents growth of the pathogen

what does MLC stand for?

minimal lethal concentration

MLC

lowest concentration of drug that kills the pathogen

what are dilution susceptibility tests for?

MIC & MLC

in dilution susceptibility- which broth or agar is minimum inhibition concentration?

lowest concentration showing no growth

if tubes showing no growth can be subcultured into drug-free medium- which broth is minimum lethal concentration?

broth from which microbe cannot be recovered

disk diffusion tests

disks impregnated with specific drugs are placed on agar plates inoculated with test microbe

zone of inhibition in disk diffusion tests

clear zones of no growth around disk

what do wider zones of inhibition indicate?

greater susceptibility of the pathogen

how are concentration gradients established in disk diffusion tests?

drug diffuses from disk into agar

can zone width be used to compare effectiveness of antibiotics?

no

what is zone width a function of?

antibiotic concentration, solubility, & diffusion rate

standardized method for disk diffusion test

kirby-bauer method

how is sensitivity/resistance determined in kirby-bauer method?

tables relating zone diameter with microbial resistance

what do table values plotted determine in kirby-bauer method?

if effective concentration of drug in body can be reached

how is the Etedt different from disk diffusion method?

uses strip instead of disk

what do Etest strips contain?

a gradient of an antibiotic

what indicated MIC in Etest?

intersection of elliptical zone of inhibition with strip

main modes of action for antimicrobial drugs

inhibitors of cell wall synthesis, protein synthesis inhibitors, metabolic agents, nucleic acid synthesis inhibition

crucial feature of penicillins

beta-lactam ring

what do penicillins inhibit?

cell wall synthesis

what is the beta-lactam ring essential for?

bioactivity

what do many penicillin resistant organisms produce?

beta-lactamase/penicillanse

what is the function of beta-lactamase/penicillinase?

hydrolyzes a bond in beta-lactam ring

what does penicillin block?

transpeptidation

transpeptidation

formation of cross-links in peptidoglycan

what does preventing the synthesis of complete cell walls lead to?

lysis of cell

what type of bacteria does penicillin act on?

growing bacteria that are synthesizing new peptidoglycan

what can some penicillins bind to?

penicillin-binding proteins

naturally occurring penicillins

narrow spectrum

which penicillins have a broader spectrum than naturally occurring ones?

semisynthetic penicillins

what makes semisynthetic more difficult for penicillinase enzymes to degrade?

bulkier side chains

cephalosporins

broad-spectrum antibiotics used by patients allergic to penicillin

drug of last resort

vancomycin

what does vancomycin inhibit?

cell wall synthesis

what is vancomycin important for treatment of?

antibiotic-resistant staphylococcal & enterococcal infections

protein synthesis inhibitors

antibiotics that bind to bacterial ribosomal proteins/rRNA

examples of protein synthesis inhibitors

aminoglycosides, tetracyclines, macolides, lincosamides, chloramphenicol

what do aminoglycosides bind to?

30s ribosomal subunit

what does binding of aminoglycosides cause?

misreading of mRNA

tetracyclines

broad spectrum & bacteriostatic

what do tetracyclines target?

30s ribosomal subunit

aminoglycoside structure

cyclohexane ring with amino acids

tetracycline structure

4 ring structure with a variety of side chains attached

macrolides structure

12-to-22 carbon lactose ring linked to 1 or more sugars

example of a macrolide

erythromycin

what does erythromycin bind to?

50s ribosomal subunit

erythromycin

broad spectrum & bacteriostatic

what are lincosamides produced by?

streptomyces bacteria

lincosamides have a broad spectrum activity against what type of microbes?

anaerobic

example of a lincosamide

clindamycin

which drug is used sparingly as it can indirectly support the growth of C. difficile?

lincosamides

what does chloramphenicol bind to?

50s ribosomal subunit

which drug is only used in life-threatening situations as it is toxic with many side effects?

chloramphenicol

what do metabolic antagonists act as?

antimetabolites

antimetabolites

antagonize or block functioning of metabolic pathways by completely inhibiting use of metabolites by key enzymes

2 characteristics of metabolic antagonists

antimetabolites & structural analogs

structural analogs

molecules that are structurally similar to & compete with naturally occurring metabolic intermediates to block normal cellular metabolism

what are sulfonamides/sulfa drugs analogs of?

PABA

PABA is used for the synthesis of what?

folic acid

what makes sulfa drugs selectively toxic?

competitive inhibition of folic acid synthesis enzymes

what does trimethoprim interfere with?

folic acid production

combining which 2 drugs increases efficacy of treatment by blocking 2 steps in folic acid pathway?

sulfa drugs & trimethoprim

nucleic acid synthesis inhibitors

fluoroquinolones & rifamycins

what do fluroroquinolones inhibit?

DNA gyrase & topoisomerases

what do rifamycins inhibit?

RNA polymerase

why are nucleic acid synthesis inhibitors not as selectively toxic as other antibiotics?

bacteria & eukaryotes do not differ greatly in the way they synthesize nucleic acids

fluoroquinolone structure

4-quinolone ring

fluoroquinolones

broad spectrum & bactericidal

2 types of drug resistance

intrinsic & acquired

intrinsic drug resistance

occurs due to a property of the microbe itself

why is mycoplasma resistant to beta-lactam antibiotics & other cell wall inhibitors?

mycoplasma bacteria lack cell walls

what type of drug resistance is the resistance of mycoplasma to beta-lactam antibiotics an example of?

intrinsic

acquired drug resistance

occurs when there is a change in the genome of a bacterium that converts it from one that is sensitive to an antibiotic to one that is resistant

drug-tolerant bacteria are also called

persisters