19 - Antibiotics Development and Mode of Action Flashcards
Physical agents
Heat, radiation (no to low selectivity)
Chemical agents
- Antiseptics, disinfectants (no to low selectivity)
- Antibiotics, synthetic antimicrobials (moderate to high selectivity)
Chemotherapy
The use of chemical agents to treat disease
Broad spectrum antibiotics
Inhibits/kills a broad range of microbes (e.g. Tetracycline inhibits Gram-ve, Gram+ve, Chlamydia, Rickettsia)
Narrow spectrum antibiotics
- Inhibits/kills narrow range of microbes (e.g. only gram +’ve or only gram -‘ve)
- specificity often due to the differences in their cell envelope structures
Static agents
- Growth is inhibited but no killing occurs
- Upon removal of the agent the microbe will recover and resume growth
- Bacteriostatic
- E.g. Chloramphenicol
Cidal agents
- Cidal agents result in irreversible microbe death, some cause cell lysis
- Bactericidal
- E.g. Penicillin
Toxic dose
Dose at which drug becomes too toxic for the host
therapeutic dose
Dose needed to treat the infection
Selective toxicity
kill or inhibit microbial pathogen but damage host as little as possible
Therapeutic index
- Toxic dose/Therapeutic dose
- The larger the therapeutic index, the better the chemotherapeutic agent
Targets of antibiotic action
- Inhibitors of protein synthesis
- Inhibitors of cell wall synthesis
- Metabolic antagonists/antimetabolites
- Inhibitors of DNA/RNA synthesis
- Cell membrane disruption
Why are antibiotics usually relatively non toxic drugs
Targets of antibiotic action are different or nonexistent in eukaryotic cells (including
humans). E.g. presence of cell wall
Selective toxicity of inhibitors of protein synthesis
Selective toxicity fairly good, as they target bacterial ribosomes, not eukaryotic ribosomes
Size of prokaryotic ribosomes
70S (50S + 30S subunit)
Size of eukaryotic ribosomes
80S (60S + 40S subunit)
Mechanism of action of aminoglycosides
- Bind to 30S subunit of ribosome, cause misreading of genetic code
- Cidal
- Broad spectrum
- E.g. Streptomycin
Mechanism of action of tetracyclines
- Bind to 30S subunit
- Static
- Broad spectrum
- E.g. Tetracycline
Mechanism of action of macrolides
- Bind to 23S rRNA of 50S subunit
- Static
- Broad spectrum
- E.g. Erythromycin
Mechanism of action of chloramphenicol
- Bind to 23S rRNA of 50S subunit
- Static
- Broad spectrum
- E.g. Chloramphenicol
Selective toxicity of inhibitors of cell wall synthesis
Selective toxicity excellent, as they target bacterial cell wall which is not present
in eukaryotic cells
Mechanism of action of penicillins (β-lactams)
- Inhibit transpeptidation enzymes (=penicillin-binding proteins) involved in cross-linking peptidoglycan cell wall
- Cidal
- Pencillin = Narrow spectrum
- Ampicillin = Broad spectrum
How does penicillin inhibit penicillin binding proteins
- Penicillins contain β-lactam ring,
which resembles the terminal D-alanyl-D-alanine of the peptides - Thus penicillins block cross-link formation
- Growing cell wall becomes less able to resist osmotic pressure - penicillins lyse growing cells
Limitations of penicillin
- Natural penicillins produced by Penicillium fungus (penicillin G, penicillin V), active against Gram positives, have limitations
- Pen G destroyed by stomach acid, somust be given by injection
- Penicillin-resistance via penicillinases soon developed
- Semisynthetic penicillins developed to overcome these limitations
Semisynthetic penicillin
- New side chains added to β-lactam ring
- Advantages include broader spectrum of
activity, acid stability so can be taken
orally, resistance to some penicillinases
Antibiotics that inhibit protein synthesis
- aminoglycosides
- tetracyclines
- macrolides
- chloramphenicol
Antibiotics that inhibit cell wall synthesis
- Penicillins
- cephalosporins
- vancomycin
Mechanism of action of cephalosporins
- contain β- lactam ring
- Broad spectrum
- Cidal
- E.g. cephalothin
- Useful if penicillin allergy
Mechanism of action of vancomycin
- Inhibits transpeptidation
- Cidal
- Narrow spectrum
- E.g. Vancomycin
What are metabolic antagonists/antimetabolites
- Structurally similar to enzyme substrate, so compete with metabolite
- Block enzyme activity, thus block a metabolic pathway
- Can have good selective toxicity as host
lacks pathway, or host enzyme differs from bacterial enzyme
Antibiotics of metabolic antagonists/antimetabolites
- sulfonamides
- trimethoprim
Mechanism of action of sulfonamides
- inhibit folic acid synthesis by competing with PABA
- Static
- Broad spectrum
- E.g. sulfanilamide
Mechanism of action of trimethoprim
- inhibits folic acid synthesis by inhibiting enzyme DHF reductase
- Broad spectrum
- Static
- E.g. Trimethoprim
Selective toxicity of inhibitors of nucleic acid synthesis
Poor selective toxicity because bacteria and eukaryotes have similar nucleic acid synthesis pathways
Antibiotics that inhibit nucleic acid synthesis
- Quinolones
- Rifampin
Mechanism of action of quinolones
- inhibit DNA gyrase: block DNA replication
- Cidal
- Broad spectrum
- E.g. Ciprofloxacin
Mechanism of action of rifampin
- Inhibits RNA polymerase: blocks RNA synthesis
- Cidal
- Narrow spectrum (TB, leprosy)
- E.g. Rifampicin
Selective toxicity of cell membrane disruptors
Poor selective toxicity as bacterial and human membranes are very similar in structure
Antibiotics that disrupt cell membrane
Polymyxins
Mechanism of action of polymyxins
- Disrupt plasma membrane, detergent-like activity
- Cidal
- Narrow spectrum
- E.g. Colistin
