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POM Test 2 > Antimicrobial Agents > Flashcards

Antimicrobial Agents Flashcards

1
Q

What are the mechanisms of action of antibacterials?

A
  1. Cell wall synthesis
  2. Membrane structure
  3. DNA sythesis
  4. Protein synthesis
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2
Q

What does selectivity mean in the context of antibiotics?

A

Killing the bacteria without doing damage to the human host.

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3
Q

What are some targets that are unique to microbes?

A
  • Cell envelope
  • Prokaryotic ribosome
  • prokaryotic nucleic acid metabolism
  • essential nutrients
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4
Q

Minimum inhibitory concentration (MIC)

A

Lowest concentration of a drug that can INHIBIT the growth of a particular bacterial species.

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5
Q

Minimum bactericidal concentration (MBC)

A

The lowest concentration of a drug that will KILL some proportion of the bacteria species.

This value will be higher than the MIC (takes more drug to kill).

(bactericidal = suicidal)

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6
Q

Bacteriostatic

A

Lowers the threshold at which the population stops growing. It will stop the bacteria from growing but will not kill them.

SMX

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7
Q

Bacteriostatic MBC and MIC relationship

A

Bacteriostatic takes much more drug to kill.

MBC >> MIC

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8
Q

Bacteriocidal MBC and MIC relationship

A

Takes same amount of drug to kill and inhibit basically.

MBC = MIC

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9
Q

Name 3 methods to determine microbial susceptibility/resistance

A
  1. A or P disk
  2. E- test/strip
  3. PCR/sequencing/etc (molecularly)
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10
Q

What is an antibiogram?

A

Summary that tracks resistant trends of microbials. Tells you the likely hood of the bugs and what they are resistant to.

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11
Q

Pharmodynamics

What is the Cmax, Cmin?

What is the AUC?

What is the relationship between T and MIC?

A
  • Cmax = maxiumum concentration that can be achieved from a given dose of drug
  • Cmin = minimum concentration of drug
  • AUC: The concentration of drug that has accumulated in that time
  • MIC is the lowest concentration of drug that will still inhibit the bacteria. We want be within the amount of time and concentration before the MIC.
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12
Q

Time- dependent killing (TDK)

What is the goal of time dependent killing?

A
  • Goal: to maximize the time that the drug concentration stays above the MIC (lowest concentration of drug that will inhibit the bacteria).
  • Specifically want the drug to be > than MIC for at least 50% of the dosing interval.
  • Examples: Penicillin (wall inhibs), Cephalosporins (wall inhibs), Macrolides (protein), Clindamycin (protein)
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13
Q

Examples of TDK

A
  • Penicillin
  • Cephalosporin
  • Macrolides
  • Clindamycin

Penny

Cephalo

Macro (instead of micro)

Linda

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14
Q

Concentration-dependent killing (CDK)

A
  • Goal: Get concentration as high as possible/maximize area under the curve.
  • Slightly different from gram + and gram -
  • Examples: Fluoroquinolones (DNA), Aminoglycosides (protein)
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15
Q

Examples of CDK

A

Examples: Fluoroquinolones, Aminoglycosides

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16
Q

Post-antibiotic effect (PAE)

A

Time it takes bacteria to return to log- phase growth following remove of antibiotic.

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17
Q

Do TDK or CDK have a longer PAE?

Do gram + or gram - have a longer PAE?

What does this mean?

A
  • CDK (Fluoroquinolones, aminoglycosides) has a longer post anitbiotic effect
  • Gram + have a longer PAE
  • This means you can extend the amount of time before the next drug is administered (reduce frequency). You can also reduce the toxicity and cost. Overall improve efficacy.
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18
Q

What does the bacterial cell envelope contain?

A
  1. Inner membrane (plasma membrane)
  2. Peptidoglycan layer
  3. Outer layer (only gram -)
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19
Q

Gram stain purple

A

purple = positive

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20
Q

Gram stain pink

A

pink = negative

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21
Q

Do gram - have an outer membrane?

A

YES

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22
Q

Do gram + have an outer membrane?

A

NO

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23
Q

Lipopolysaccharide

A
  • Outside of outermembrane of gram - cells is LPS = lipopolysaccharide
  • Has a component called Lipid A that is an endotoxin.

(put the - in the sac)

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24
Q

Describe the peptidoglycan in a gram - cell

A

The peptidoglycan is NOT as thick and is between the inner membrane and outer membrane.

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25
Q

Lipoteichoic acid (LTA)

A

Lipoteichoic acid (LTA) is on the cell membrane of gram + cells.

(teic people are very +)

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26
Q

Describe the peptidoglycan in a gram + cell.

A
  • Many layers of peptidoglycan on the one cell membrane. These layers are sugars joined together and they give structure and rigidity to gram + cells.
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27
Q

Peptidoglycan (aka murein)

  • What is peptidoglycan made of?
  • What kind of sugars are in peptidoglycan?
  • Which sugar is the peptide cross-linked to?
  • What gives pepetidoglycan its ridgidity?
A
  • Peptidoglycan is made of peptides and sugars.
  • NAM (N-acetylmuramic acid) and NAG (N-acetylglucosamine) disaccharide
  • The peptide is cross linked to NAM (N-acetylmuramic acid).
  • The cross- linked peptide gives peptidoglycan its ridgidity.
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28
Q

Transpeptidation

A

Putting amino acids together in peptidoglycan.

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29
Q

Transglycolation

A

Putting sugars together in peptidoglycan.

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30
Q

B-lactams

  • What do they inhibit
  • What is the main example?
A
  • B-lactams inhibit transpeptidation. This means they interfer with the linking of proteins to each other in the peptidoglycan layer.
  • The main example B-lactam is penicillin (Fleming).
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31
Q

Where does penicillin (B-lactam) bind?

A

Penicillin binds to the penicillin binding proteins (PBP).

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32
Q
  • What is Penicillin Binding Proteins (PBP)?
  • What does PBP usually bind to?
  • How does it accidentally bind penicillin? What happens when it does?
A
  • Protein for peptidoglycan. Penicillin binding proteins are transpeptidases. This means that they link peptides together. (They also have transglycolase activity)
  • PBP will bind the last two aa of the PG chain, D-ala, D-ala.
  • PBP accidently binds penicillin because penicillin looks like D-ala, D-ala. The enzyme will bind to penicillin and its activity will be inhibited.
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33
Q

Is it easier for B-lactams to reach gram + peptidoglycan or gram - peptidoglycan?

A

Gram + peptidoglycan because it is thicker and right on the surface of the cell membrane.

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34
Q

What are two main classes of B-lactams?

A
  1. Penicillin (Penicillin G)
  2. Cephalosporin (Cephalosporin C)
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35
Q

Summary Slide: What are some ways that bacteria resist anti-biotics? (anti-biotic resistant mechanisms)

A
  1. Enzymatically inactivate the drug (B-lactamases)
    1. B-lactamases destroy the B-lactam
    2. B-lactamases are encoded on mobile genetic elements so they can be easily shared
  2. Alter the drug target
    1. Change the structure of the enzyme that the drug binds to
    2. Can occur by mutation or horizontal exchange (mecA or MRSA)
  3. Alter the drug exposure
    1. Decreased uptake: prevent the drug from getting in
      1. gram - will change size of pores for nutrients to get in but not drugs
    2. Increased efflux (or influx rate)
      1. pump that flushes everything back out so drug cannot say long
36
Q

B-lactamases

  • What do they do?
  • What is the effect on bacteria that have B-lactamases?
A
  • B-lactamases cleave the B-lactam ring on penicillin so that penicillin becomes penicolloic acid and can no longer bind to PBP because its structural recognition is destroyed.
  • Bacteria that have B-lactamases can resist penicillin and other B-lactam antibiotics.
37
Q

ESBL- extended spectrum B-lactamases

  • What do they fight against?
  • What pt mutations are they derived from?
A
  • B-lactamase
  • results in activity against many b-lactams specifically extended spectrum cephalosporins
  • derived from pt mutations in TEM/SHV
38
Q

Metal-Dependent/NDM-1

A

B-lactamase that is clinically relevant

39
Q

Clavaunic acid

  • What does it do?
  • What does it look like?
A
  • Clavuanic acid targets b-lactamases and will deactivate them.
  • Looks like a b-lactam
    • B-lactamases will bind to b-lactam to try to cut the ring but Clavuanic acid will trick them and inactivate them.
40
Q

What is an alternative penicillin-resistant PBPs?

How do they arise?

A
  • An antibiotic resistant mechanisms that alters the penicillin drug target
  • It is a PBP that still has transpeptidase activity but low affinity for B-lactams.
  • They can arise through mutation or aquired horizontally.
41
Q

Fitness cost

A
  • Everytime a bacteria is resistant to something there is a cost. For example the bacteria will not grow as well over the hours.
42
Q

What is resistance?

Which are the antibiotics to choose?

A

Bacterial growth in the presence of antibiotic.

Choose antibiotics with higher finesscost for resistance.

43
Q

Altered drug exposure - Altered penicillin transport

What are two ways of altering penicillin transport?

A
  1. Decrease the membrane permeability (gram - only)
    1. How? by changing size of pores
  2. Increased efflux
    1. pump
44
Q

Describe the different mechanisms of resistance in this picture

A

What type of bacterial cell: Hypothetical gram - (can see outer membrane)

  1. Channels that are normally wide open but in presence of drug you can change structure of porin so the drug cannot get in as easily (decreased membrane permeability -> only with gram -)
    1. Genes that code for porin proteins that effect susceptibility
  2. B lactamase very useful they will inactivate the drug
  3. Drug target PBP (see mutation in PBP so now drug doesn’t bind)
  4. See on the left mechanism of multiple bacterial proteins
    1. Multi protein structure that can span the whole difference between inner and outer membrane and bugs can be shuttled out of bacterial cell
45
Q

Glycopeptides

  • What are they?
  • What do glycopeptides target?
  • What is the main example?
A
  • Glycopeptides are an antibiotic.
  • Glycpopeptides inhibit the transglycosylation (putting two sugars together) of the peptidoglycan layer. (glycopeptides inhibit transglycosylation)
  • The main example of glycopeptides are vancomycin (vanco glyco).
46
Q

Where does vancomycin (glycopeptide) bind?

A
  • Vancomycin binds to the D-ala D-ala termination peptide part because in order for sugars to be linked the enzyme that links sugars has to find the D-ala-D-ala peptide. Vancomycin covers this and transglycosylation cannot continue.
47
Q

Vancomycin resistant mechanisms

  • Can the D-ala-D-ala have a spontaneous mutation so the vancomycin cannot bind? (alter drug target)
  • Can the bacteria inactivate drug?
  • Can bacteria alter drug exposure?
A
  • The D-ala-D-ala cannot have spontaneously mutation because it is not encoded by a gene. A gene has to encode an enzyme that puts the two aa together therefore it is not just one mutation in the DNA.
    • HOWEVER, can alter this enzyme to make D-ala-D-lac that vancomycin cannot bind to.
  • There are no known enzymes that can inactivate glycopeptide antibiotics.
  • Vancomycin is used to treat Gram + infections so cannot have decreased uptake.
48
Q

D-ala-D-lac

A
  • Resistance mechanisms for bacteria against vancomycin
  • Peptidoglycan is made normally.
  • High fitness cost to do this and it does not make peptidoglycan that is as strong.
49
Q

Bacitracin

Phosphomycin

Cycloserine

A

Other antibiotics that have to do with peptidoglycan and cell wall.

50
Q

Mycobacterium species

  • What are examples?
  • What is hte waxy long-chain branched hydrocarbons called?
  • What type of stain?
A
  • Examples of Mycobacterium species include M. tuberculosis and M. leprae
  • Mycolic acid
  • Acid fast stain
51
Q

Isoniazid

A

Drug that inhibits mycolic acid synthesis in the mycobacterial cell walls.

(z = mycolic acid)

52
Q

Ethambutol

A

Inhibits arabinotransferase which create arabinogalactan (a sugar like molecular that adds to the structural agility) of mycobacterium.

53
Q

Lipopeptides

  • What are lipopeptides?
  • Where and how do they act (and what type of bacteria)?
  • Example?
  • How do they differentiate bacterial cell membranes from host cell membranes?
A
  • Lipopeptides are an antibiotic.
  • Lipopeptides act on the cell membrane of gram + bacteria, work through the peptidoglycan layers and poke the cell membrane and make pores that ultimately lyse the bacteria.
  • Example is Daptomycin
  • They differentiate it because they bind to phosphatidyl glycerol (PG) which is abundant in only bacterial cell membranes.
54
Q

What can lipopeptides NOT treat? and why?

A

Lipopeptides cannot treat pneumonia because there is peptidylglycan in the lung surfactant (it will attack this).

55
Q

What do bacterial folate synthesis inhibitors do? and why?

A

Bacterial folate synthesis inhibitors inhibit the enzymes in the pathway to make tetrahydrofolic acid (THF) in bacteria. They do this because THF helsp synthesize DNA, RNA and proteins in bacteria.

56
Q

What are two examples of bacterial folate synthesis inhibitors?

A

Sulfonamides (top enzymes)

Trimethoprim (bottom enzymes)

57
Q

Sulfonamides

  • What are they?
  • How do they do this?
  • Are they bacteriostatic or bacteriocidal?
  • Active against what bacteria?
  • Example?
A
  • Sulfonamides are antibiotics that inhibit folate synthesis in bacteria (because folate synthesis leads to RNA, DNA, and protein synthesis in baciteria)
  • They target the enzyme DHPS.
  • Bacteriostatic
  • G+ G- and protozoa
  • Example is smx or sulfamethoxazole
58
Q

Sulfamethoxazole (smx)

A

Sulfonamide that inhibits folate synthesis in bacteria.

59
Q

What are three ways that bacteria get resistance against sulfonamides?

A
  1. Alter the drug target
    1. The drug target for sulfonamides is the dhps protein in folate synthesis. Spontaneous mutations can occur in the dhps gene or horizontal acquisition of alternate dhps encoded on mobile element.
  2. Swam the system
    1. Increase the production of the folate precursor PABA.
  3. Altered Drug Exposure
    1. decrease the uptake.
60
Q

Why would you use combinatorial therapy?

A
  • To prevent the emergency of resistance
  • Etiology unknown
61
Q

What is drug synergy?

A

Each drug works better the the presence of the other drug. You can get a better outcome with a lower dose of the drugs.

62
Q

Trimethoprim (tmp)

  • What is it and what does it do?
  • How does it do this?
  • What is it often used together with?
  • What type of relationship do they have and what is the advantage of using both at once.
A
  • Trimethoprim is an antibiotic that inhibits folate synthesis in bacteria (which is a precurser for RNA, DNA and protein synthesis in bacteria).
  • Trimethoprim specifically inihibits DHFR.
  • Trimethoprim (tmp) is used with sulfamethoxazole (smx)
  • Synergisic (use lower dose of both and more effective)
    • Smx becomes bactericidal
    • targets 2 steps in same pathway reduces likelihood of resistance from bacteria
63
Q

Quinolones/Floroquinolones

  • What is it/What do they do?
  • How do they do this?
  • Are they bacteriostatic or bactericidal?
  • What bacteria do they work on?
  • What is an example?
A
  • Quinolones/floroquinolones are antibiotics that inhibit prokaryotic DNA synthesis.
  • They do this by inhibiting DNA gyrase (aka topoisomerase II) and topoisomerase IV
  • They are bactericidal
  • They can work on both but G- > G+
  • Examples are ciprofloxacin.
64
Q

When fluoroquinolones inhibit DNA gyrase what happens?

A

When fluroquinolones inhibit DNA gyrase (topoisomerase II) they induce damage.

65
Q

When fluoroquinolones inhibit topoisomerase IV what do they do?

A

Topoisomerase IV causes circular bacterial genomes to separate. Therefore fluroquinolones inhibits topoisomerase IV from having newly replicated chromonsomes in daughter cells.

66
Q

Resistance to quinolones

  • How is the drug target altered?
  • How is the drug exposure altered?
A
  • The drug target is altered by chromosomal mutations in gyrase and topoisomerase genes.
  • The drug exposure is altered
    • Decreased uptake via mutations in gram - porin proteins
    • increased efflux
    • cross resistance between quinolones and other antibiotics and host-derived antimicrobial factors - multidrug resistance (MDR)
67
Q

What type of antibiotic inhibits mRNA snthesis in bacteria?

A

Rifamycin

68
Q

Rifamycin

  • What is rifamycin and what does rifmycin do?
  • Is it batericidal or bacteriostatic
  • What does it bind to? How?
  • What is an example?
A
  • Rifamycin is an antibiotic that inhibits mRNA synthesis in bacteria.
  • Rifamycin can be bactericidal or bacteriostatic dependentin on concentration (used for tuberculosis).
  • Rifamycin binds to bacterial DNA-dependent RNA polymerase because it has a higher afinity to that than human DNA-dependent RNA polymerase
  • An example is rifampin
69
Q

Rifampin

A

Example of a rifamycin which inhibits mRNA synthesis.

70
Q

How does bacteria become resistance against rifamycin?

(Altered drug target)

A

Bacteria alter their drug target which mean that they will have spontaneous mutations in RNA polymerase gene. Therefore rifamycin is rarely used because resistance arises quickly.

71
Q

Nitroimidazole

  • What are they and what do they do?
  • Are they bactericidal or bacteriostatic?
  • What do they work against?
  • Describe how they work.
  • What is an example?
A
  • Nitroimidazoles are an antibiotic that damages DNA using reduced drug metabolites that are highly reactive radicals.
  • Nitroimidazoles are bactericidal
  • They work against anaerobic microbes and protozoa.
  • They first are prodrugs, which mean they must be converted by microbial enzyme to an active form (ferredoxin). The activated drugs form toxic free radicles that will damage bacterial DNA.
  • Example is metronidazole
72
Q

How do bacteria resist against nitroimidazoles?

A

Bacteria will create mutations in microbial enzymes that convert the produrc to the active compound.

73
Q

What class is penicillan and cephalosporin?

A

B- lactam

74
Q

What inhibits B-lactamase?

A

clauvanic acid

75
Q

Vancomycin belongs to what class?

A

glycopeptides

76
Q

Glycopeptide

A

vancomysin

77
Q

Mycolic acid mycobacterial

A

isoniazid

78
Q

Arabinotransferase mycbacterial

A

ethambutol

79
Q

Gram + affect cell membrane

A

lipopeptide

80
Q

Affects DHPS enzyme in folate synthesis

A

sulfonamide, sulfamethozadole

81
Q

affects DHFR enzyme in folate synthesis

A

trimethoprim

82
Q

Sulfamethoxazole (smx)

A

inhibits folate synthesis specifically the DHPS enzyme

can combine with trimethoprim for synergy

83
Q

Fluoroquinolones subclass

A

ciprofloxacin

84
Q

rifamycin subclass

A

rifampin

85
Q

what does rifampin affect?

A

mRNA synthesis

86
Q

what damages DNA?

A

nitroimolazole

metronidazole

87
Q
A

POM Test 2 (8 decks)

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