Lecture 13: Antibacterials Flashcards
Salvarsan
identified by Ehrich to treat syphillis
3 classifications for bacteria
- shape
- aerobic or anaerobic
- gram staining
Gram positive bacteria
thick peptidoglycan layer in cell wall but no outer membrane
stain purple with crystal violet dye
Gram negative bacteria
extra outer membrane
also have peptidoglycan wall but less thick
tougher to treat
Disc diffusion method
test sensitivity of bacteria to drug
Bactericidal vs Bacteriostatic
bactericidal: kill bacteria (irreversible)
bacteriostatic: blocks reproduction of bacteria (reversible after agent removed)
Penicillin
bactericidal
lactam ring binds and inhibit DD transpeptidase
prevent crosslink and formation of new cell wall
orally bioavailable
2 resistance mechanism against penicillin
- evolved thicker outer membrane
- acquire penicillinase gene (inactivate penicillin)
Vancomycin
bactericidal
inhibit cell wall synthesis by directly binding to D-Ala-D-Ala peptides
prevent incorporation into a growing peptide chain
blocks elongation and crosslinking
deliver intravenously
Resistance mechanism to vancomycin
bacteria change precursor D-Ala-D-Ala to D-Ala-D-Lac
Polymyxins
bactericidal
directly binds to LPS in outer cell membrane
cause holes
leakage
delivered orally
Tetracyclines
broad spectrum antibiotic
directly binds to 30S subunit of bacterial ribosome
block binding of tRNA
inhibit bacterial protein synthesis
bacteriostatic
orally bioavailable
Azithromycin
macrolide-based antibiotic
bind 23s rRNA of the 50s ribosomal subunit
blocks translocation during protein synthesis
bacteriostatic
orally bioavailable
Linezolid
binds to 23s rRNA of 50S subunit
prevent formation of 70S initiation complex
bacteriostatic
very bioavailable in oral and IV
broad spectrum
Ciprofloxacin
bactericidal
binds to DNA gyrase
block proper compaction and storage of DNA
good oral bioavailability
do not take with milk
Ca2+ can chelate the drug and prevent absorption
Metronidazole
Bactericidal
PRODRUG
activated by bacterial enzyme to generate a toxic radical
widespread DNA damage
high bioavailability
adverse reactions: radical gets out of bacterial cell and damage healthy cells
Trimethoprim
bacteriostatic
binds to bacterial DHFR enzyme
inhibit folic acid synthesis
block DNA synthesis
TERATOGENIC, do not use in pregnancy
5 steps in bacteriophage replication cycle
- attachment
- penetration
- replication
- maturation
- release (lysis ,explode)
2 states of bacteriophage
lytic - actively reproducing, bursting and killing bacteria
lysogenic - not actively killing bacterial cells (prophage)
Phage therapy
orally as pill with antacid to gut
0.1% transcytoses
very selective but hard to find correct strain match (use cocktails)
4 ways of bacteriophage resistance from bacteria
- mutations of outer receptor so phage cannot attach
- SIE (superinfection exclusion) system - block entry of phage by inactivating critical enzymes
- methylation of bacterial DNA, DNA cleavage not allowed for phage DNA
- adaptive immunity from CRISPR
Cas13
cuts RNA instead of DNA
have collateral damage (nuclease domain remains active after first cut)
bactericidal
Anti-CRISPR proteins (ACRs)
used by bacteriophage
block crRNA loading
acetylates PAM sensing lysine residue
turn off CRISPR system
4 Considerations of using Cas9 and Cas13
- can cause immune reaction towards cas9 and cas13
- off target DNA-RNA cleavage
- can cause antimicrobial resistance genes from repair mechanism
- hard to deliver through bacterial cell wall and membrane
