BIOl 3200 mehari exam 4 (antimicrobial therapy)

antimicrobial vs antibiotic

antimicrobials - anything that can kill microbes

antibiotics - products of other organisms known to kill bacterial cells

leading cause of pneumonia in humans

S. pneumoniae

75% of all antibiotics are used in

animal feed

60-70% of nosocomial staphylococcus infects are a result of

MRSA (methicillin resistant S. aureus)

Ernest Duchesne

proposed that bacteria and molds engaged in a perpetual battle for survival

looked at the effect of fungus

Alexander Fleming

rediscovered penicillin

the mold was identified as Penicillium notatum

the penicillin we use today came from a moldy melon that has strains of penicillin

Howard Florey and Ernst Chain

purified penicillin

Gerhard Domagk

discovered sulfa drugs

discovered the first commercially available antimicrobial drug

look at antimicrobials, not antibiotics

Selman Waksman + student Albert Schatz

father of antibiotics

discovered 20+ antibiotics

- most successful is Streptomycin

discovered streptomycin from Streptomycin griseus in soil

two criteria for antimicrobial therapy

antibiotic must affect target organism

it must not affect humans

broad spectrum antibiotics

an antibiotic that is able to affect both Gram negative and Gram positive bacteria

narrow spectrum antibiotics

sensitive to only a few types of bacteria

penicillin spectrum

narrow?? (in class he said broad)

is more effective against Gram positive than Gram negative cells because Gram negative have an extra lipid layer that makes their cell wall more protected

bactericidal

antibiotic that kills bacteria

bacteriostatic

antibiotic that inhibits bacterial growth

cannot kill organism, if removed then organism will resume growth

minimum inhibitory concentration (MIC)

smallest concentration of drug that visibly inhibits growth

may still have living (nongrowing) organisms

only requirement is that tube growth is NEGATIVE

minimal lethal concentration (MLC)

lowest concentration of drug that kills pathogen

requires tube growth to be NEGATIVE and subculture plate to be NEGATIVE

MLC/MIC ratio

MLC > MIC

Kirby-Bauer

test is used to determine the susceptibility of a microorganism to an antibiotic

zone of inhibition cannot be assumed as susceptible or not, must be measured, and compared to chart

leading causes of death

CVD > cancer > covid19 > accidents > stroke

penicillin inhibitor type

cell wall

cephalosporins inhibitor type

cell wall

vancomycin inhibitor type

cell wall

cell wall inhibitors - goal

inhibit peptidoglycan synthesis

interfere with synthesis

cell wall - peptidoglycan makeup

NAG and NAM peptide

cell wall - transglycosylases

enzymes that form the B 1,4 linkages between NAG-NAM

attaches precursors to existing cell wall structure

cell wall - transpeptidases

cross-linking of linear peptidoglycan chains

forms amino acid links between NAM sugars of different layers

penicillin and cephalosporin - inhibition

mimicry via beta lactam ring that resembles D-Al-D-Al piece of peptidoglycan

inhibit the cross-bridge formation by transpeptidase!!

penicillin and cephalosporin - affect to humans

no toxicity

humans lack cell walls

peptidoglycan does not exist in mammalian cells

semisynthetic penicillin differ in

R groups

vancomycin - inhibition

blocks transglycosylases and transpeptidases by binding to D-Ala-D-Ala terminal

blocks transglycosylation!!

"last resort" for penicillin resistant Gram positive organisms

given intravenously due to poor absorption

- to big to diffuse through Gram negative cell wall

vancomycin - affect to humans

no toxicity

polymyxins inhibitor type

cell membrane

gramicidin inhibitor type

cell membrane

cell membrane inhibitors - availability

fewest available antibiotics due to similarity between bacteria and human cell membranes

cell membrane inhibitors - goal

interfere with cell membrane

gramicidin - inhibition

forms cyclic cation channel

allows ions leakage out of cell to disrupt membrane polarity

lyse

polymyxin (colistin) - inhibition

detergent like

destroyed cell membrane

lyse

only topical use

gramicidin and polymyxin - affect to human

toxicity

humans have similar membranes to bacteria

applied topically

- internal application would be harmful

quinolone inhibitor type

DNA replication

DNA synthesis & integrity

sulfonamide (sulfa drugs) inhibitor type

metabolic

DNA synthesis & integrity

DNA synthesis & integrity inhibitor - goal

inhibit DNA synthesis

quinolone (fluoroquinolones) - inhibition

block bacterial DNA gyrase and therefore prevents DNA replication

quinolone (fluoroquinolones) - affect to humans

no toxicity

humans have a different topoisomerase

DNA gyrase is unique to bacteria

sulfonamide - inhibition

mimicry via SFA that resembles PABA for folic acid synthesis

inhibits folic acid synthesis which is needed for DNA synthesis

sulfonamide - affect to humans

no toxicity

humans are able to get folic acid from dietary sources

humans do not synthesize folic acid in the body

rifamycin B (rifampin) inhibitor type

RNA polymerase

RNA polymerase inhibitors - goal

inhibit transcription

most active agent against growing bacteria

actinomycin D inhibitor type

RNA polymerase

RNA polymerase inhibitors are all

bactericidal

rifamycin B (rifampin) - inhibition

binds to beta subunit of RNA polymerase

does not allow RNA polymerase to bring in more nucleotides to elongate chain

prevents the elongation step of transcription

rifamycin B (rifampin) - affect to humans

no toxicity

humans have a different RNA polymerase

actinomycin D - affect to humans

toxic

we all share the same DNA

actinomycin D - inhibition

binds to DNA from any source

prevents the initiation step of transcription

aminoglycosides (streptomycin) inhibitor type

30S ribosome subunit

protein synthesis

tetracyclines inhibitor type

30S ribosome subunit

protein synthesis

macrolide (erythromycin) inhibitor type

50S ribosome subunit

protein synthesis

chloramphenicol inhibitor type

50S ribosome subunit

protein synthesis

clindamycin and metronidazole inhibitor type

50S ribosome subunit

protein synthesis

30S & 50S ribosome subunit/protein synthesis inhibitors - goal

inhibit translation of mRNA

affects 30S and 50S subunit

aminoglycosides (streptomycin) - inhibition

causes the translational misreading of mRNA

tetracyclines - inhibition

blocks the binding of charged tRNA to the A-site of the ribosome

is bacteriostatic

macrolide (erythromycin) - inhibition

inhibits translocation

chloramphenicol - inhibition

inhibits peptide transferase activity

clindamycin and metronidazole - inhibition

bind at the same ribosomal site as chloramphenicol

active in anaerobic environments

30S & 50S ribosome subunit/protein synthesis - affect to humans

can be toxic

due to human relation to our inherited mitochondria from ancient bacteria

tetracycline - affect to humans

toxicity

mitochondrial ribosomes of humans are susceptible

common cold caused by

Rhinovirus

rhinovirus and antibiotics

no antibiotic designed for bacteria can touch it

why are there fewer antiviral agents

antivirals target host cell machinery and have bad side effects

hard to get selective toxicity to kill viruses and nothing else

antivirals - goal

inhibit DNA synthesis

amantadine inhibitor type

antiviral, preventing virus uncoating/release

neuraminidase inhibitor type

antiviral, preventing virus uncoating/release

xofluza inhibitor type

antiviral, preventing virus uncoating/release

amantadine - inhibition

prevents entry of virus into host cell

- is intact before virus enters the cell

- finds virus before cell entry

- prevents viral uncoating

has developed resistance

neuraminidase - inhibition

prevents release of mature viruses

traps virus inside infected human cell

tamiflu was previously the most commonly prescribed for the flu

xofluza - inhibition

targets viral RNA polymerase

inhibits the activity of influenza cap-dependent endonuclease, which will prevent cap-snatching and stop viral replication

most effective against growing number of flu viruses

zidovudine - inhibition

mimicry via zidovudine (DNA with -N3 ) that resembles thymine (DNA with -OH) for normal DNA polymerase to use to bind nucleotides too

causes growing chain termination, inhibit new DNA synthesis

inhibits reverse transcriptase

most common anti-HIV drug

zidovudine inhibitor type

antiviral, prevents DNA synthesis

zidovudine - affect to humans

can be toxic but human DNA polymerase has proofreading ability

why are fungal infections more difficult to treat than bacterial infections

fungi are eukaryotes, and so selective toxicity issues arise

fungi have an efficient drug detoxification system that modifies and inactivates many drugs

fungal physiology is more similar to that of humans than bacterial physiology is

are unable to have selective toxicity

antifungal - affect to humans

toxic

both human and fungal cells are eukaryotes

antifungal superficial mycoses

treated topically

antifungal deep mycoses

treated systematically

why are there fewer antiviral drugs than antibacterial drugs

there are fewer viral specific drug targets in viruses

viruses are intracellular

ALL antibiotics listed on the lecture slides are bactericidal except

TETRACYLINES

erythromycin

macrolide

4 key steps of peptidoglycan synthesis of Gram positive bacteria

amino acids are added to NAM

D-Ala peptide attach

NAM pentapeptide transfer to bactoprenol on Gram positive cell membrane

NAG links to NAM

- NAM contains the side chain

NAM-NAG chain flips to be on the outside of the cell membrane

transglycosylase attaches new disaccharide units to the NAM-NAG chain

pentaglycine connects L-Lys one one side and penultimate D-Ala on the other

antibiotics that affect peptidoglycan synthesis in Gram positive bacteria

penicillin, cephalosporins, and vancomycin inhibit peptide cross-linking

interfere with PBPs

- pencillin mimicry prevents PBP function of peptide cross linking by binding to PBP active site