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Flashcards in Antimicrobial Drugs - Dupre Deck (65)
1

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

2

Acids and alkalis

Prevents growth
Denatures proteins by changing pH

3

Heavy metals

Inhibit bacterial growth
Denatures proteins

4

Halogens

Hypochlorous acid used in pools with chlorine
Oxidize cell components in absence of organic matter

5

Alcohols

70% alcohols
Denature proteins when mixed with water

6

Phenols

Disrupts membranes, denatures proteins and inactivated enzymes

7

Oxidizing agents

Disrupt disulphide bonds and structure of memrbane

8

Alkylating agents

Disrupts structure of proteins and nucleic acids

9

Dyes

Some interfere with cell replication or block cell wall synthesis

10

Soaps and detergents

Lower surface tension
Make microbes accessible to other agents

11

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

12

Bactericidal

Cells are killed

13

Bacteriostatic

Growth is arrested

14

Therapeutic window of antibiotics

Usually very safe
Large window
Main adverse effects are allergic responses (NOT toxicity) or disturbances of the normal bacterial flora

15

MIC

Minimal inhibitory concentration
Takes about 3 days to reach between doses

16

Antibiotics

Not the same as antimicrobial drugs
Agent produced by one organism that have some toxic or inhibitory effect on cancer, bacteria etc

17

Bactericidal antibiotics

Drugs that cause the death of the bacteria
Required if the patient is immunosuppressed

18

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

19

Features to attack on bacterial cells

1. Completely unique structure (ie. peptidoglycan)
2. Pathways that are absent in mammalian cells (ie. dihydropteroate synthetase, which produces folic acid which we get from out diet)
3. Structure that are different between humans and bacterial cells (ie. ribosomes)
4. Enzymes that differ between humans and bacterial cells
5. Cellular constituents that are different in microorganisms (ie. lipid ergosterol)
6. Cellular constituents that are enriched in microorganisms (ie. lipid phosphatiduylethanolamine)

20

Where antibiotics work

1. Cell wall synthesis
2. Folic acid metabolism
3. Cytoplasmic membrane structure
4. DNA gyrase
5. RNA elongation
6. DNA-directed RNA polymerase
7. Protein synthesis (50S or 30S inhibition or tRNA)

21

Structure of bacterial cell wall

Peptidoglycan causes structure and rigidity
Protection

22

Peptidoglycan

Fibrous scaffold in the wall
Cross-linked network of polysaccharides (repeats of certain amino sugars) by polypeptides

23

Penicillin-binding protein

Enzyme that helps make scaffold in peptidoglycan
At least 6 different types

24

Beta lactamase

Enzyme
Causes resistance to drugs, breaks down common penicillin-like drugs
Susceptible drugs have beta lactic group in their structure

25

Porins

Protein pores that pierce the membrane

26

Transpeptidation

Step catalyzed by PBPs
Inhibitors: penicillins, cephalosporins, carbepenems

27

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

28

Potential problems of antibiotics

1. 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)
2. Interference by beta lactamases

29

Narrow spectrum penicillins

Penicillin V ( better than G because G breaks down in acid)

30

Extended spectrum penicillins

Amoxicillin
Better absorbed, longer half life

31

Cephalosporins

4 generations, each becoming more resistance to beta lactamases, better activity against gram-negative bacteria, better ability to cross into tissue spaces

32

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

33

Vancomycin

Binding to growing peptide chain
Prevents subsequent ability to crosslink

34

Bacitracin

Mixture of cyclic peptides
Works inside the cell to block cell wall synthesis

35

Antibiotics that block protein synthesis

Erythromycin and other macrocodes
Tetracyclines
Amino glycosides
Chloramphenicol
Streptomycin

36

Combining antibiotics

By blocking different steps, more likely for antibiotics to work overall

37

Streptomycin

Amino glycoside
Changes shape of 30S protein
Causes code on mRNA to be read incorrectly

38

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)

39

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

40

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

41

Macrolides

Ie. erythromycin
Work best with gram positive
Bacteriostatic

42

Clarithromyin

Chemically modified from erythromycin, with additional methyl group
Improved acid stability
Improved oral absorption
Most active against gram positive anaerobes

43

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

44

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

45

Why are there multiple antibiotics that block protein synthesis?

1. Different chemically, affecting their stability and absorption
2. Interfere at different sites on the bacterial ribosome, which means they have different therapeutic actions

46

Folic acid

Most bacteria make their own
Made from PABA via DHPS
Then reduced from folate to THF by DHFR

47

Sulfonamides

Target DHPS
Structure similar to PABA

48

Trimethoprim

Blocks DHFR

49

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)

50

DNA gyrase

Cuts DNA temporarily during DNA unwinding
Bacterial topoisomerase type II
Inhibitors cause replication arrest

51

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

52

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

53

Advantages of using antimicrobial drugs in combinations

Wider spectrum for mixed infections
Reduced dose for individual agents
Synergism between antibiotics

54

Risks of using antimicrobial drugs in combinations

Increased possibility of adverse reactions
Antagonism between antibiotics
Greater risk of antibiotic resistance

55

Septra

Combination of sulfamethoxazole and trimethoprim
Both bacteriostatic, together became bactericidal

56

Antibiotic resistance

1. Beta-lactamase
2. Mutations in proteins
If antibiotics are used too freely
Bacteria are agile

57

Bacterial adaptation

1. Reduced entry of the antibiotic into the bacteria
2. Increased amount of target protein
3. Lower binding to altered target protein
4. Enzyme breakdown of the drug

58

Sulfanamide resistance

1. Decreased permeability of the cell membrane
2. Bacteria produce a form of dihyropteroate synthetase (DHPS) that binds to sulfanamide poorly
3. Increase production of PABA by the bacteria

59

Trimethoprim resistance

1. Decreased permeability of the cell membrane
2. Bacteria produce a form of dihyrofolate reductase (DHFR) that binds trimethoprim poorly
3. Bacteria produce more DHFR

60

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

61

Antifungals in oral candidiasis

Candidiasis is most common type of oral fungal infection
Oral ketoconazole, oral fluconazole, intravenous amphotericin B

62

Oral ketoconazole

Treatment in oral candidiasis
Potentially hepatotoxic

63

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)

64

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

65

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