22 Antibiotic Medications

Question 1

Bacteria have two different types of cell wall, how is this used by scientists?

Answer 1

Feature is used to classify bacteria into gram-positive and gram-negative

Question 2

Where does gram-negative and gram-positive come from?

Answer 2

Reaction different bacteria cell walls have to a gram stain:

• Old imaging technique used to label and identify bacteria strains
  
  • Because of structure of cell membrane
• Gram-negative - appear pink after washing the stain off
  
  • have thin cell wall with few layers of peptidoglycan surrounded by second lipid membrane containing lipopolysaccharides and lipoproteins
• Gram-Positive - appear dark purple after staining
  
  • thick cell wall with many layers of peptidoglycan

Question 3

What is the difference between the celll-walls in Gram-positive and Gram-negative bacteria?

Answer 3

• Gram-positive bacteria:
  
  • Possess a thick cell wall with many layers of peptidoglycan (polysaccharide chain)
  • Gram-stain binds to the peptidoglycan layer
• Gram-negative bacteria
  
  • Relatively thin cell wall with few layers of peptidoglycan surrounded by a second lipid membrane containing lipopolysaccharides
  • less peptidoglycan + extra lipid membrane = absorbs less stain

Question 4

Peptidoglycan structure consists of ______ strands made of alternating ___________ and ____________ residues cross-linked by peptides

Answer 4

Peptidoglycan structure consists of glycan strands made of alternating N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) residues cross-linked by peptides

Question 5

What part of the bacteria cell membrane has the greatest contribution to the overall structure and shape of the bacterium?

Answer 5

Peptide cross-linkers between glycan strands

Question 6

Individual strands of glycan are polymerized by the enzyme ________ into the peptidoglycan chain

Answer 6

Individual strands of glycan are polymerized by the enzyme glycosyltransferase (GT) into the peptidoglycan chain

Question 7

What enzyme is responsible for generating the peptide cross-links that provide the structure to the bacteria cell membrane?

Answer 7

Transpeptidase (TP)

• target of many antibiotics (aka penicillin-binding protein)

Question 8

What are four terms used to describe the efficacy and potency of antibiotics?

Answer 8

1. Spectrum of activity
2. Bacterial sensitivity
3. Therapeutic index
4. Ability to penetrate

Question 9

What is Spectrum of activity?

Answer 9

Spectrum of activity can be narrow or broad depending on the number of different bacterial species against which they exhibit useful activity

Question 10

What is bacterial sensitivity?

Answer 10

Sensitivity measured by assessing the ability of the bacterial strain to replicate following antibiotic exposure

• Bacteriocidal antibiotic leads to permanent loss of replicative ability
• Bacteriostatic antibiotic leads to temporary loss of growth and replication that returns following the removal of antibiotics

Question 11

________\_ antibiotic leads to permanent loss of replicative ability

Answer 11

Bacteriocidal antibiotic leads to permanent loss of replicative ability

Question 12

_________\_ antibiotic leads to temporary loss of growth and replication that returns following the removal of antibiotics

Answer 12

Bacteriostatic antibiotic leads to temporary loss of growth and replication that returns following the removal of antibiotics

Question 13

What is the difference between broad spectrum and narrow spectrum antibiotics?

Answer 13

Broad-spectrum: Kills off/targets a variety of bacterial species

Narrow-spectrum: targets 1-a few species of bacteria

Question 14

What is therapeutic index?

Answer 14

Ratio of minimum concentration likely to produce an adverse effect to the minimum concentration needed to produce a desired effect

• Wide Therapeutic index = safer

Question 15

What is Ability to penetrate?

Answer 15

Ability of drug to get to target;

Delivery of antibiotic to site of infection is most difficult challenge of antibiotic delivery

Question 16

What are four classes of antibiotics?

Answer 16

1. Cell wall inhibitors
2. Folic acid
3. DNA synthesis inhibitors
4. Protein synthesis inhibitors

Question 17

How do antibiotics not target “self” (eukaryotic cells)

Answer 17

Antibiotics are designed to target pathways that are unique to bacteria (ie not found in eukaryotic cells)

Question 18

What was the first cell-wall inhibitor developed?

Answer 18

Penicillin

-discovered by alexander fleming in 1928 - produced by fungus penicillium notatum

Question 19

What antibiotic was derived from the fungus Acremonium in 1945 (similar to penicillin in that it is a cell-wall inhibitor)

Answer 19

Cephalosporins

Question 20

Penicillins and cephalosporins are called ________ because they have an unusual 4-member ring

Answer 20

Penicillins and cephalosporins are called beta-lactams because they have an unusual 4-member ring

Question 21

How do Penicillins and cephalosporins work?

Answer 21

• Inhibit cell wall synthesis by inhibiting an enzyme (DD-transpeptidase (aka penicillin-binding protein)) responsible for cross-linking components of the cell wall (bacteriocidal)

Question 22

Are penicillins and cephalosporins bacteriocidal or bacteriostatic?

Answer 22

Bacteriocidal - permanent destruction of the bacteria (interfering with outer structure of cell kills bacteria)

Question 23

Do penicillins and cephalosporins target gram-negative or gram-positive bacteria?

Answer 23

Originally were only effective against gram-positive but successive generations of cephalosporins have increased activity against gram-negative (although still more effective against gram-positive bacteria)

• Why?
  
  • because gram-positive bacteria have an exposed outer peptidoglycan layer = easily accessible

Question 24

What are beta-lactamases?

Answer 24

Bacterial enzymes (penicillinases, cephalosporinases) made by most staphylococci and many gram-negative organisms that hydrolyze the beta-lactam ring of certain penicillins and cephalosporins; confer resistance

• defense mechanism
• ARMS RACE

Question 25

What are beta-lactamase inhibitors? Provide an example.

Answer 25

Potent inhibitors of beta-lactamases used in combinations to protect hydrolyzable penicillins (antibiotics) from inactivation eg: **Clavulanic acid**

Question 26

What drug named in lecture is NOT a beta-lactam but, like beta-lactams, inhibits the peptidoglycan cross-linking?

Answer 26

**Vancomycin** is not a beta-lactam but inhibits peptidoglycan cross-linking

Question 27

\_\_\_\_\_\_\_\_ is produced in nature by **actinobacteria species**, *Amycolatopsis orientalis*, commonly found in soil

Answer 27

_Vancomycin_ is produced in nature by **actinobacteria species**, *Amycolatopsis orientalis*​, commonly found in soil

Question 28

Make a flowchart of three bacterial cell wall inhibitors: _1_ _2_ _3_ Narrow and/or broad Species

Answer 28

1. Penicillins * Narrow spectrum 1. Penicillinase susceptible 2. Penicillinase Resistant 2. Cephalosporins * Narrow Spectrum * 1st generation * Wider spectrum * 2nd, 3rd, 4th generations 3. Miscellaneous * Carbapenems * Aztreonam * Vancomycin

Question 29

Why do bacteria need folic acid?

Answer 29

Bacteria use folic acid to synthesize nucleic acids that make up their DNA (pathway unique to bacteria)

Question 30

What is the synthesis pathway that bacteria use to make DNA?

Answer 30

1. p-Aminobenzoic acid (PABA) - precursor for folate 2. converted to **Dihydrofolic acid** using **Dihydropteroate synthase** 3. Converted to **Tetrahydrofolic acid** by **Dihydrofolate reductase** 4. Purines 5. DNA

Question 31

What is Para-aminobenzoic acid (PABA)?

Answer 31

Nutrient obtained from the environment that is the precursor for folate in bacteria - converted into dihydrofolic acid and then to tetrahydrofolic acid by dihydropteroate synthase and dihydrofolate reductase respectively

Question 32

Eukaryotes don't have PABA and must get folic acid from \_\_\_\_\_

Answer 32

Eukaryotes don't have PABA and must get folic acid from _diet_

Question 33

What do folic acid inhibitors target?

Answer 33

The folate synthesis pathway in bacteria

Question 34

\_\_\_\_\_\_ and _______ resemble PABA and dihydrofolic acid respectively and interfere with PABA metabolic pathways

Answer 34

_Sulfonamides_ and _trimethoprim_ (folic acid inhibitors) resemble PABA and dihydrofolic acid respectively and interfere with PABA metabolic pathways

Question 35

Which folic acid inhibitors compete with PABA

Answer 35

_Sulfonamides_ compete with PABA

Question 36

Which folic acid inhibitors compete with Dihydrofolic acid?

Answer 36

**Trimethoprim** competes with dihydrofolic acid for the enzyme: Dihydrofolate reductase

Question 37

Which two folic acid inhibitors are usually given together and why?

Answer 37

Sulfonamides and trimethoprim because they block different steps in the synthesis pathway

Question 38

Bacteria make protein from ______ within the bacterial _________ complex. This is unique to bacteria (eukaryotes use 80s ribosomal complex) and so allows targeting by \_\_\_\_\_\_\_\_\_\_\_\_

Answer 38

Bacteria make protein from _mRNA_ within the bacterial _70s ribosomal_ complex. This is unique to bacteria (eukaryotes use 80s ribosomal complex) and so allows targeting by _Protein Synthesis inhibitors_

Question 39

_\_\_\_\_\_\_\__ transfers an amino acid to the growing amino acid chain (**transpeptidation**)

Answer 39

_tRNA (t6)_ transfers an amino acid to the growing amino acid chain (**transpeptidation**)

Question 40

What is the name of the process in which amino acids are added to a growing amino acid chain?

Answer 40

Transpeptidation

Question 41

\_\_\_\_\_\_\_\_\_\_ and _________ bind to the 50s subunit and block transpeptidation

Answer 41

_Chloramphenicol_ and _Macrolides_ bind to the 50s subunit and block transpeptidation

Question 42

*Chloramphenicol* and *Macrolides* bind to the and block transpeptidation

Answer 42

*Chloramphenicol* and *Macrolides* bind to the _50s subunit_ and block transpeptidation

Question 43

\_\_\_\_\_\_\_\_ bind to the 30s subunit and prevent binding of incoming tRNA

Answer 43

_tetracyclines_ bind to the 30s subunit and prevent binding of incoming tRNA

Question 44

*tetracyclines* bind to the and prevent binding of incoming tRNA

Answer 44

*tetracyclines* bind to the _30s subunit_ and prevent binding of incoming tRNA

Question 45

How do the effects of Chloramphenicol, Macrolides and Tetracyclines differ?

Answer 45

Chloramphenicol and Macrolides bind to the 50s subunit and **block transpeptidation** Tetracyclines bind to the 30s subunit and **prevent binding of incoming tRNA** **image:** C-triangle = chloramphenicol M-triangle = Macrolides T-triangle = tetracycline

Question 46

Like tetracyclines, ________ bind to the 30s ribosomal subunit

Answer 46

Like tetracyclines, _aminoglycosides_ bind to the 30s ribosomal subunit

Question 47

What are three effects of aminoglycosides (where do they bind)?

Answer 47

Aminoglycosides bind the 30s ribosomal subunit and: 1. Block the initiation of the complex * prevent two subunits from coming together 2. Cause misreading of the code on the mRNA template * wrong aa is added (missense) (or no aa at all - nonsense) 3. inhibit translocation * process of releasing protein from ribosome

Question 48

Why dont antibiotics inhibit protein synthesis in human cells as well?

Answer 48

* Selectivity is provided by differences in protein synthesis enzymes between humans and microorganisms and the rapid growth of bacteria * eg: chloramphenicol doesn't bind to the 80s ribosomal rna of mammalian cells, only the 70s ribosomal rna of bacteria * eg mammalian cells cannot synthesize folic acid from PABA

Question 49

What is bacterial resistance?

Answer 49

The ability of the microbe to resist the effects of antibiotics * arms race between antibiotics and bacteria * Consequence of evolution via natural selection * constant division = increased opportunity for mutation = some mutations may confer a survival advantage against antibioties = survive and divide

Question 50

What are four ways in which bacteria are known to develop bacterial resistance?

Answer 50

1. Drug inactivation or modification 2. Alteration of binding site 3. Alteration of metabolic pathways 4. Reduced drug accumulation

Question 51

"Beta lactamases are enzymes produced by bacteria that inactivate antibiotics" What type of bacterial resistance is this?

Answer 51

Drug inactivation or modification

Question 52

Provide an example of "Alteration of binding site" which leads to bacterial resistance

Answer 52

Alteration of **penicillin-binding proteins** (aka DD-transpeptidase) in methicillin-resistant staphylococcus (MRSA)

Question 53

Provide an example of "Alteration of metabolic pathways" leading to bacterial resistance

Answer 53

Sulfonamide resistant bacteria begin to use pre-formed folic acid from the environment rather than making it from PABA

Question 54

Provide an example of reduced drug accumulation leading to bacterial resistance?

Answer 54

Develop efflux pumps to actively remove antibiotic from bacterial cell (similar to p-glycoprotein pumps in the brain that pump drug out of brain)

Question 55

Why might antibiotic use led to gastrointestinal distress?

Answer 55

Because, particularly for broad spectrum, they can target the normal gut flora thus interfering with bacterial environment of the body * probiotic products can be used in conjunction to help limit/alleviate this

Question 56

What affects might antibiotics have on the skin?

Answer 56

Adverse skin reactions ranging from mild rash to photosensitivity. - use photoprotection (sunscreen) to help prevent UV damage - Stevens-johnson syndrome - Toxic epidermal necrolysis

Question 57

What are Stevens-johnson syndrome and toxic epidermal necrolysis?

Answer 57

rare conditions in which the skin becomes detaches from the underlying tissue and sloughs off the body