Principles of antimicrobial therapy Flashcards
Targets of drug action
Enzymes Receptors Ion channels Transporters targets in host cell to later function
Immunity
Body’s ability to recognise and remove non-self material
Action of anti-microbial drugs
Ability to recognise and destroy non-self cells
What is chemotherapy based on?
Selective toxicity
What is selective toxicity?
Causes greater harm to micro-organism than host
Anti-microbial drugs must have limited toxicity but good selectivity
To increase efficacy= increase dose but efficacy and toxicity must be balanced
Chemotherapeutic index formula
Toxic Dose (lowest)/Therapeutic dose
Chemotherapeutic index meaning
The ratio of the minimal effective dose of a chemotherapeutic agent to the maximal tolerated dose
4 types of anti-microbial drugs
Anti-bacterial
Anti-fungal
Anti-protozoan
Anti-helminthic
Class I pathways that antimicrobial drugs target
Reactions that use glucose/other carbon sources to make ATP/substrates needed for class II reactions
Class II pathways
Pathways that use ATP and class I substrates to make small molecules e.g amino acids, nucleotides
Class III pathways
Convert small class II molecules into macromolecules e.g proteins, nucleic acids, polysaccharides, peptidoglycan
Name of a class II antimicrobial drug
Sulfonamide
What the pro drug of sulfonamide that is metabolized in the body to produce sulfonamide?
Prontosil
Sulfonamide mechanism of action
Competitive inhibitor of dihydropteroate synthetase
This enzyme normally produces folic acid
Prevent bacterial DNA synthesis and replication
Why can bacteria synthesise folate but humans can’t?
Bacteria have the enzyme dihydropteroate synthetase enzyme but humans don’t
What does dihydrofolate reductase catalyse?
Formation of tetrahydrofolate from dihydrofolate
What antimicrobial drugs prevent action of dihydrofolate reductase?
Trimethoprim
Methotrexate
Pyrimethamine
Mechanism of action of trimethoprim, methotrexate and pyrimethamine
(for trimethoprim) Type= antifolate antibacterial agent
Interaction- dihydrofolate reductase
Reversible inhibitor of dihydrofolate reductase
Tetrahydrofolate cant be made which is essential in making thymidine, nucleic acids and proteins (methionine)
so inhibits bacterial DNA synthesis
Killing bacteria
Example of a class III antimicrobial drug
Penicillin
What class of drug is penicillin?
Beta-lactam
Is penicillin broad/narrow spectrum antibiotic?
Narrow spectrum
Examples of Beta-Lactam drugs
Penicillins
Monobactams
Carbapenems
Cephalosporins
Bacteria cell wall peptidoglycan synthesis
Penicillin binding protein in cell wall e.g transpeptidase enzyme normally catalyses cross linking of peptidoglycan chains by binding to D-ALA D-ALA by transpeptidation reaction
What does beta-lactam do?
Inhibits peptidoglycan cell wall synthesis
Beta lactam mechanism of action
Beta-lactam ring mimics D-ALA D-ALA
beta lactam forms a covalent bond with amino aciid serine of transpeptidase enzyme
This inhibits transpeptidase carrying out the transpeptidation reaction required for peptidoglycan synthesis
no cell wall= lysis of bacteria by autolytic enzymes e.g autolysins
Antibiotics that inhibit cell wall synthesis
Vancomycin
Bacitracin
Cycloserine
Class III Anti-bacterial drugs can prevent synthesis of what?
Ribosomes
Eukaryotic ribosomes
80s
Large subunit= 60s
Small subunit= 40s
Prokaryotic ribosomes
70s
Large subunit= 50s (23sRANA)
Small subunit= 30s (16sRNA)
Why are ribosomes a good target for anti-bacterial drugs?
Bacteria ribosomes are different to eukaryotic ribosomes
What drugs target 30s subunit of bacteria ribosomes?
Aminoglycosides
Tetracyclines
Mechanism of action of Aminoglycosides
Targets 16sRNA of 30S subunit
Irreversibly bind to specific 30S-subunit proteins and 16S rRNA
Induces misreading of mRNA
incorrect amino acids are inserted into the polypeptide leading to non-functional or toxic peptides
halts protein synthesis
Mechanism of action of Tetracyclines
Broad spectrum
Passively diffuses through porin channels in the bacterial membrane
Reversibly binds to the 30S ribosomal subunit
preventing the attachment of aminoacyl-tRNA to the ribosomal A site (mRNA-ribosome complex)- in initiation of translation
Inhibiting bacterial growth by inhibiting translation
Which anti-bacterial drugs target the 50S large subunit of bacterial ribosomes?
Macrolides
Fusidic acid
Macrolides mechanism of action
Broad spectrum
Bind to 50s subunit- to 23 S rRNA of 50S
Preventing the translocation of the elongation factor G (EF-G) from the ribosome
Inhibits polypeptide translocation and assembly of 50s subunit.
Problem with bacterial ribosome-targeting drugs?
We have the same ribosomes in our mitochondria as bacteria
Name of anti-bacterial drugs that target DNA arrangement?
Quinolones
Quinolone mechanism of action
Prevents and inhibits DNA gyrase and topoisomerase from supercoiling and unwinding DNA
Inhibiting DNA replication
Example of a quinolone
Ciprofloxacin
Anti-bacterial drugs that target DNA synthesis
Quinolones
Metronidazole
Anti-bacterial drug that target RNA polymerase
Rifampicin (inhibits RNA polymerase)
Anti-bacterial drug that targets bacteria cytoplasmic phospholipid membrane
Polymyxins
Anti-bacterial drugs that target protein synthesis (50s inhibitors)
Erythromycin
Lincomycin
Anti-bacterial drugs that target protein synthesis (30s inhibitors)
Aminoglycosides
Tetracycline
What are broad-spectrum drugs?
Active against a wider number of bacterial types
Used to treat a wide variety of infectious diseases
Useful when bacteria agent is unknown but likely to fall within a set of a certain species
What are narrow spectrum drugs?
Used for specific infection when causative organism is known
Advantage of narrow spectrum over broad spectrum drugs
Narrow spectrum drugs won’t kill as many of the normal microorganisms in the body like broad spectrum drugs do
so narrow spectrum drugs are less likely to produce GI side effects and/or residual drug reisistant strains
What type of bacteria do polymyxins target?
Gram negative bacteria
Examples of polymyxins
Polymyxin B Polymyxin E (colistin)
Mechanism of action of polymyxins (colistin)
Colistin binds to LPS and phospholipids in outer membrane of gram-negative bacteria
Competitively displaces Ca2+ and Mg2+ from phosphate group of lipids in OM
Disrupts outer membrane= lysis
What type of bacteria does vancomycin target?
Gram positive bacteria
What is streptomycin an example of?
Aminoglycoside
Inhibits protein synthesis (30s)
What type of cell wall do mycobacterium have?
Arabinogalactan
Anti-bacterial drug that targets gram negative bacteria and mycobacterium
Streptomycin
Why are anti-bacterial drugs good?
Clear difference between eukaryotic and bacterial cells
so easier to target bacterial cells
Problem with anti-fungal drugs?
Fungi are also eukaryotic cells so little differnece between our cells and fungal cells
What can anti-fungal drugs target in fungi?
Cell membrane
Cell division
What anti-fungal drug targets fungi cell membrane?
Flucanozole
What do fungi have in their cell membrane instead of cholesterol?
Ergosterol
Fluconazole mechanism of action
Type- antifungal
Interacts- fungal cytochrome P450 dependent enzyme
Selective inhibitor of fungal cytochrome P450 dependent enzyme
This enzyme normally converts lanosterol to ergosterol
Inhibiting ergosterol synthesis
Disruption structure and function fungal membrane
What anti-fungal drug disrupts cell structure/division in fungi?
Flucytosine
Flucytosine mechanism of action
Type- antimetabolite
Fluctyosine is converted into fluorouracil (5FU)
5FU is converted into 5-fluorodeoxyuridylic acid (5dUMP)
5dUMP inhibits thymidylate synthase from converting dUMP to dTMP
preventing DNA synthesis
Anti-viral drugs
Target various stages in virus’ life cycle
What part of virus’ life cycle do anti-viral drugs target?
Entry into host cells
Nucleic acid replication
Viral protein synthesis
Virus exiting host cell
Virus life cycle
- Virus attaches to receptor on host’s surface
- Virus attaches and enters host cell
- Uncoating of virus
- Genome replication of virus
- Protein and RNA synthesis of virus
- Assembly and maturation
- Released from host cell by neuraminidase
What do anti-viral ion channel blockers do?
Prevent uncoating of virus in host cell
What do integrases do?
Allow viral genome to integrate into host cell
Anti-viral drugs that inhibit attachment and entry of virus into host cell
Maraviroc
Enfuvirtide
Anti-viral drugs that block ion channels
Amantadine
Rimantadine
Anti-viral drugs that inhibit DNA/RNA polymerase from being made
Acyclovir
Zidovudine
Anti-viral drug that inhibits integrase enzymes
Raltegravir
Anti-viral drugs that inhibit proteases
Saquinavir
Ritonavir
Antiviral drugs that inhibit neuraminidase
Zanamivir
Oseltamivir
What does viral neuraminidase do?
Allows virus to be released from host cell
Viral entry inhibitor
Chloroquine
Ribavirin and Favipiravir
Inhibit viral RNA dependent RNA polymerase
Hydroxychloroquine
Inhibit viral entry
Proteolysis
Spread viral proteins
Inhibitors of proteolysis
Lopinavir
Ritonavir
Ideal drug target
System in the infectious microorganism that doesn’t exist or exists in a different form in the host cell
Class I biochemical processes
Common in most organisms so not a good target
Class II and III
More likely to differ between organisms so a good target
What are the mechanisms responsible for resistance of bacteria to anti-microbial drugs?
- Inactivating enzymes- beta lactamases break down beta lactam antibiotics (e.g monobactams)
- Decreased drug accumulation by:
- Changing surface proteins e.g porins- bulk transporters- allow material to enter cells. Reduce no. of proins= reduce drug uptake into bacteria
- Efflux pump- ejects drug out of cell (U-turn) - Altering binding site- drug cant bind to it
- Development of alternative metabolic pathways - e.g sulfonamides and trimethoprim
How do bacteria spread resistance?
- Spontaneous mutation- occurs as cells replicate
some bacteria acquired resistance
drug eliminates sensitive organisms
resistant ones proliferate - Gene transfer/ Transferred resistance- transfer of plasmid (extrachromosomal DNA)
3.Pilli of bacteria can also help spread resistance
