Antimicrobial Drugs - Dupre Flashcards
Antimicrobial chemical agents
Produced by one organism that have some toxic or inhibitory effect on anther organism or cell
CAN be toxic to cells too
Acids and alkalis
Prevents growth
Denatures proteins by changing pH
Heavy metals
Inhibit bacterial growth
Denatures proteins
Halogens
Hypochlorous acid used in pools with chlorine
Oxidize cell components in absence of organic matter
Alcohols
70% alcohols
Denature proteins when mixed with water
Phenols
Disrupts membranes, denatures proteins and inactivated enzymes
Oxidizing agents
Disrupt disulphide bonds and structure of memrbane
Alkylating agents
Disrupts structure of proteins and nucleic acids
Dyes
Some interfere with cell replication or block cell wall synthesis
Soaps and detergents
Lower surface tension
Make microbes accessible to other agents
Selective toxicity
Using toxic drugs, as long as they are more toxic to your target than to normal tissues
Ie. antimicrobial drugs or anticancer drugs
Bactericidal
Cells are killed
Bacteriostatic
Growth is arrested
Therapeutic window of antibiotics
Usually very safe
Large window
Main adverse effects are allergic responses (NOT toxicity) or disturbances of the normal bacterial flora
MIC
Minimal inhibitory concentration
Takes about 3 days to reach between doses
Antibiotics
Not the same as antimicrobial drugs
Agent produced by one organism that have some toxic or inhibitory effect on cancer, bacteria etc
Bactericidal antibiotics
Drugs that cause the death of the bacteria
Required if the patient is immunosuppressed
Bacteriostatic antibiotics
Drugs that inhibit the growth of the bacteria
Growth resumes when drug is removed
Success depends on where being an effective immune reposne
Features to attack on bacterial cells
- Completely unique structure (ie. peptidoglycan)
- Pathways that are absent in mammalian cells (ie. dihydropteroate synthetase, which produces folic acid which we get from out diet)
- Structure that are different between humans and bacterial cells (ie. ribosomes)
- Enzymes that differ between humans and bacterial cells
- Cellular constituents that are different in microorganisms (ie. lipid ergosterol)
- Cellular constituents that are enriched in microorganisms (ie. lipid phosphatiduylethanolamine)
Where antibiotics work
- Cell wall synthesis
- Folic acid metabolism
- Cytoplasmic membrane structure
- DNA gyrase
- RNA elongation
- DNA-directed RNA polymerase
- Protein synthesis (50S or 30S inhibition or tRNA)
Structure of bacterial cell wall
Peptidoglycan causes structure and rigidity
Protection
Peptidoglycan
Fibrous scaffold in the wall
Cross-linked network of polysaccharides (repeats of certain amino sugars) by polypeptides
Penicillin-binding protein
Enzyme that helps make scaffold in peptidoglycan
At least 6 different types
Beta lactamase
Enzyme
Causes resistance to drugs, breaks down common penicillin-like drugs
Susceptible drugs have beta lactic group in their structure
Porins
Protein pores that pierce the membrane
Transpeptidation
Step catalyzed by PBPs
Inhibitors: penicillins, cephalosporins, carbepenems
Penicillin
Different modifications of core structure
Penicillin V, Amoxicillin
1. Crosses wall into bacterium
2. Binds to PBP - inhibits
3. Peptidoglycan is not made
4. Cell looses rigidity
5. Fluid inside exerts outward pressure: lysis
Potential problems of antibiotics
- Getting across the outer lipid membrane into gram-negative bacteria (this is why many antibiotic work against gram positive instead gram negative, unless the negative have porins)
- Interference by beta lactamases
Narrow spectrum penicillins
Penicillin V ( better than G because G breaks down in acid)
Extended spectrum penicillins
Amoxicillin
Better absorbed, longer half life
Cephalosporins
4 generations, each becoming more resistance to beta lactamases, better activity against gram-negative bacteria, better ability to cross into tissue spaces
Carbapenems
ie. Imipenem
Penicillin-like antibiotics int which the sulphur atom of the penicillin structure is replaced with carbon
Altered spectrum
resistant to beta-lactamases
Vancomycin
Binding to growing peptide chain
Prevents subsequent ability to crosslink
Bacitracin
Mixture of cyclic peptides
Works inside the cell to block cell wall synthesis
Antibiotics that block protein synthesis
Erythromycin and other macrocodes Tetracyclines Amino glycosides Chloramphenicol Streptomycin
Combining antibiotics
By blocking different steps, more likely for antibiotics to work overall
Streptomycin
Amino glycoside
Changes shape of 30S protein
Causes code on mRNA to be read incorrectly
Tetracyclines
Interfere with attachment of tRNA to mRNA-ribosome complex
Broad spectrum (bacteria, mycoplasma, some protozoa)
Bacteriostatic
Resistance is common
Differ mainly in their pharmokinetics
Chelate divalent metal ions
Absorption affected by milk and antacids
Accumulate in developing bone and teeth
Should not be used in second half of pregnancy and young children
Also cause gastrointestinal irritation (mucosa and flora)
Erythromycin
Binds to 50s portion, preventing translation moment of ribosome along mRNA
Base is somewhat unstable in acid conditions
Food reduces absorption
Works well against gram positive organism
Generally poor against gram negatives
Useful in penicillin resistant infections
Chloramphenicol
Broad spectrum
Bacteriostatic
Binds to 50S portion and inhibits formation of peptide bond
Adverse effects: bone marrow disturbances, common interactions with other drugs, gray baby syndrome
Macrolides
Ie. erythromycin
Work best with gram positive
Bacteriostatic
Clarithromyin
Chemically modified from erythromycin, with additional methyl group
Improved acid stability
Improved oral absorption
Most active against gram positive anaerobes
Azithromycin
Further modified from clarithromycin, with additional lactone ring
Excellent tissue penetration
Release from tissue only slowly
Longer half-life
Best activity against gram negative anaerobes
Also acts against spirochetes
Less likely to become involved in drug interactions
Aminoglycoside
ie. entamicin, streptomycin
Used mostly against gram-negative enteric bacteria
Oral doses are very poorly absorbed
Usually given intramuscularly or intravenously
Ototoxic and nephrotoxic
Hexose ring bonded to amino sugars with glycosidic bonds
Blocks formation of initiation complex
Miscoding in the polypeptide chain
Block of translocation
Why are there multiple antibiotics that block protein synthesis?
- Different chemically, affecting their stability and absorption
- Interfere at different sites on the bacterial ribosome, which means they have different therapeutic actions
Folic acid
Most bacteria make their own
Made from PABA via DHPS
Then reduced from folate to THF by DHFR
Sulfonamides
Target DHPS
Structure similar to PABA
Trimethoprim
Blocks DHFR
Sulfonamides and trimethoprim together
Synergistic bactericidal
More effective than either drug alone
Still works if resistance develops to one drug
At dose ratio 1:5 (gives plasma ratio of 1:20)
DNA gyrase
Cuts DNA temporarily during DNA unwinding
Bacterial topoisomerase type II
Inhibitors cause replication arrest
Fluoroquinolones
Block DNA gyrase enzyme
ie. ciprofloxacin
Early drugs were quinolones, but were fluorinated as it made them more useful against systemic infections
Many respiratory pathogens are now resistant
Polymyxins
Detergent-like properties Interferes with integrity of bacterial cell membrane Binds to phosphatidylethanolamine Causes disruption of the bacterial cell membrane Toxic if systemic (we have PE too) Resistance rarely develops Hypersensitivity is rare Used topically
Advantages of using antimicrobial drugs in combinations
Wider spectrum for mixed infections
Reduced dose for individual agents
Synergism between antibiotics
Risks of using antimicrobial drugs in combinations
Increased possibility of adverse reactions
Antagonism between antibiotics
Greater risk of antibiotic resistance
Septra
Combination of sulfamethoxazole and trimethoprim
Both bacteriostatic, together became bactericidal
Antibiotic resistance
- Beta-lactamase
- Mutations in proteins
If antibiotics are used too freely
Bacteria are agile
Bacterial adaptation
- Reduced entry of the antibiotic into the bacteria
- Increased amount of target protein
- Lower binding to altered target protein
- Enzyme breakdown of the drug
Sulfanamide resistance
- Decreased permeability of the cell membrane
- Bacteria produce a form of dihyropteroate synthetase (DHPS) that binds to sulfanamide poorly
- Increase production of PABA by the bacteria
Trimethoprim resistance
- Decreased permeability of the cell membrane
- Bacteria produce a form of dihyrofolate reductase (DHFR) that binds trimethoprim poorly
- Bacteria produce more DHFR
Double antibiotic resistance
Way to eradicate resistance strain infections
Link two of them: beta-lactam antibiotic with quinolone
If betalactamase is present, quinolone is released, if not, beta-lactam antibiotic does the work
Antifungals in oral candidiasis
Candidiasis is most common type of oral fungal infection
Oral ketoconazole, oral fluconazole, intravenous amphotericin B
Oral ketoconazole
Treatment in oral candidiasis
Potentially hepatotoxic
Oral fluconazole
Treatment in oral candidiasis
Potentially hepatotoxic (alternative to ketoconazole, less toxic)
Azole fungal drug
Works through ergosterol
Less toxic than polyene antifungals
Acts by inhibiting fungal cytochrome P450 (lower affinity for human P450)
Intravenous amphotericin B
Treatment in oral candidiasis
Significantly toxic and may cause renal damage
Polyene macrolide antibiotics
Lipophilic on one side and hydrophilic on the other, makes pore
Ergosterol
Main target of antifungals
Lipid in fungal cell membrane (equivalent to our cholesterol)
Antifungals bind and form pores that leak out contents or bind enzymes that important in making ergosterol
