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BIOSCI 106 > Section 5: Nutrition and Antibiotics > Flashcards

Section 5: Nutrition and Antibiotics Flashcards

1
Q

Vitamins are a…

A

Micronutrient

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2
Q

Micronutrients - role

A

Play a vital role in human metabolism since they’re involved in almost every known biochemical reaction and pathway

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3
Q

Synthesising vitamins - animals

A

Higher animals have lost the capacity to synthesise vitamins during the course of evolution

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4
Q

Vitamins: Biosynthetic pathways - complexity

A

Can be complex, leading to the suggestion that it’s biologically more efficient to ingest vitamins than to synthesise the enzymes required to construct them from simple molecules
This efficiency comes at a cost of dependence on other organisms for chemicals essential for life

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5
Q

Macronutrients

A

Carbs, fats, proteins

In humans, the catabolism of macronutrients to supply energy is an important aspect of nutrition

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6
Q

Micronutrients

A

Vitamins and minerals
Either our bodies can’t synthesise them or they can’t synthesise them in amounts sufficient for our needs –> must obtain vitamins from dietary sources

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7
Q

Vitamins are necessary for…

A

Metabolic processes

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8
Q

Vitamins - amount

A

Required in small amounts, i.e. µg to mg

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9
Q

Vitamins are the building blocks for…

A

Larger molecules

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10
Q

Vitamins - energy yield

A

Don’t yield energy when degraded

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11
Q

Humans require at least __ vitamins in their diet

A

12

By contrast, E. Coli only require glucose and organic salts, and make everything else they need

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12
Q

Vitamins - groups

A

Water-soluble:
Vitamin B group
Vitamin C

Fat-soluble:
Vitamin A
Vitamin D
Vitamin E
Vitamin K
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13
Q

Water soluble vs fat soluble vitamins - structure

A

Water soluble: highly variable in structure

Fat soluble: structurally similar - all isoprenoid compounds

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14
Q

Water-soluble vitamins

A 
Structural variation
Functional uniformity
Require modification for function - precursor molecules (except vitamin C)
Carry mobile metabolic groups;
- activated carriers
- function as coenzymes (vit B)
Readily excreted
Easily degraded - don't tend to build up easily in the cell
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15
Q

Fat soluble vitamins

A

Structurally more similar
Functionally diverse - vit A and D more like hormones
Not easily absorbed from food sources - more difficult to get in sufficient quantity
Generally not activated carriers / coenzymes
Can be toxic in excess (vit A)

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16
Q

Almost all activated carriers are derived from _______

A

Vitamins

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17
Q

Activated carriers: ATP - group carried and vitamin precursor

A

Group carried: Phosphoryl

Vitamin precursor: not a vitamin precursor

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18
Q

Activated carriers: NADH and NADPH - group carried and vitamin precursor

A

Group carried: e-

Vitamin precursor: Nicotinate (niacin) - vitamin B3

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19
Q

Activated carriers: FADH2 - group carried and vitamin precursor

A

Group carried: e-

Vitamin precursor: Riboflavin - vitamin B2

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20
Q

Activated carriers: Coenzyme A - group carried and vitamin precursor

A

Group carried: acyl

Vitamin precursor: Pantothenate - vitamin B5

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21
Q

Activated carriers: Tetrahydrofolate - group carried and vitamin precursor

A

Group carried: 1C units

Vitamin precursor: Folate - vitamin B9

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22
Q

Many of the B vitamins are _________

A

Activated carriers

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23
Q

What is an activated carrier

A

A molecule that carries a group that is then transferred to other molecules/groups

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24
Q

B vitamins: Riboflavin (B2) - coenzyme, typical reaction type, consequences of deficiency

A

Coenzyme: FAD
Reaction: ox-red
Consequences: cheilosis and angular stomatitis (lesions of mouth), dermatitis

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25
Q

B vitamins: Nicotinic acid (niacin) - coenzyme, typical reaction type, consequences of deficiency

A

Coenzyme: NAD+
Reaction: ox-red
Consequences: pellagra (dermatitis, depression, diarrhea)

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26
Q

B vitamins: Folic acid - coenzyme, typical reaction type, consequences of deficiency

A

Coenzyme: tetrahydrofolate
Reaction: transfer of 1C components; thymine synthesis
Consequences: anemia, neural-tube defects in development

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27
Q

Deficient in vitamin B2 generally results in…

A

Inflammatory conditions

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28
Q

Non-coenzyme vitamins: Vitamin C - function and deficiency

A

Function: antioxidant
Deficiency: scurvy (swollen and bleeding gums, subdermal haemorrhaging)

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29
Q

Vitamin C AKA…

A

Ascorbic acid

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30
Q

Non-coenzyme vitamins: Vitamin A - function and deficiency

A

Function: vision, growth, reproduction
Deficiency: night blindness, cornea damage, damage to respiratory and GI tract

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31
Q

Non-coenzyme vitamins: Vitamin D - function and deficiency

A

Function: regulates calcium and phosphate metabolism
Deficiency: rickets (children); skeletal deformities, impaired growth
osteomalacia (adults); soft, bendy bones

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32
Q

Vitamin C - antioxidant

A

Reducing agent

Itself is oxidised

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33
Q

Which vitamins function like hormones

A

A and D

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34
Q

Forms of ascorbic acid

A

Ascorbate: the ionised form of ascorbic acid

Dehydroascorbic acid: the oxidised form of ascorbate

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35
Q

Humans can’t synthesise vitamin C

A

Human cells can’t perform the crucial last step of vit C biosynthesis; the conversion of L-gulono-γ-lactone into ascorbic acid, which is catalysed by gulunolactone oxidase

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36
Q

Humans can’t synthesise vitamin C - gulonolactone oxidase

A

Gene that codes for gulonolactone oxidase is present in human genome, but is inactive due to accumulation of several mutations that have turned it into a non-functional pseudogene

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37
Q

Possible (evolutionary) advantages of being unable to synthesise vitamin C

A

Reaction catalysed by gulono oxidase also produces H2O2
Levels of vit C regulates a key stress-induced transcription factor HIF1 α
Pseudogenes can have a significant role in epigenetic regulation of gene expression

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38
Q

Possible (evolutionary) advantages of being unable to synthesise vitamin C - H2O2

A

Highly chemically reactive
Can cause damage to cells
Loss of vitamin C is balanced with not making such a reactive species

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39
Q

Possible (evolutionary) advantages of being unable to synthesise vitamin C - HIF1 α

A

Hypoxia inducible factor α
Activated by low O2 or limited vit C –> indicates nutritionally deficient –> turns on HIF1 α transcription gene –> invokes stress response
Fine tuning based on nutritional status

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40
Q

Possible (evolutionary) advantages of being unable to synthesise vitamin C - pseudogenes

A

Some pseudogenes can have roles affecting gene expression of other genes

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41
Q

Major causes of nutritional disease

A

Famine - leads to raft of diff nutritional deficiencies

Vit C deficiency - 2nd most common

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42
Q

Nutritional disease: Age of sail vs today

A

2 million sailors died of vit C deficiency

Today ~1/100,000 people

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43
Q

Nutritional disease: who is more prone

A

Elderly
Mentally ill patents
Alcoholics (decrease absorption and storage)

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44
Q

Scurvy - symptoms

A 
Swollen, bleeding gums (gum disease)
Poor wound healing
Bleeding under skin
Bruising
Changes to hair
Lethargy
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45
Q

Scurvy - experiment

A

12 sailors with scurvy, divided into groups of 2, were kept on same diet and salted meals, and given 6 diff supplements;

  1. cider
  2. elixir of vitriol
  3. vinegar
  4. seawater
  5. lemons and oranges
  6. an electuary (medicinal paste)
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46
Q

Scurvy - experiment results

A

The sailors receiving the lemons and oranges quickly improved while the cider appeared to offer modest benefit and the rest had no relief
But, it didn’t prove what it was in the lemon and oranges that helped prevent scurvy

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47
Q

Vitamin C and wound healing

A

After 6 months of no vit C diet, there’s complete lack of healing; large space occupied by an organised blood clot
After 10 days of intravenous vit C, complete healing of both original wound and that of the biopsy

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48
Q

Vitamin C - electrons

A 
Electron donor (reducing agent / antioxidant)
Probs all of its biochemical and molecule roles can be accounted for by this functionality
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49
Q

Ascorbates interacts with enzymes having either…

A

Monooxygenase or dioxygenase activity

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50
Q

What does ascorbic acid accelerate

A

Hydroxylation in numerous biosynthetic pathways

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51
Q

Ascorbic acid - acts as an e- donor for…

A

8 enzymes in humans

3 participate in hydroxylation required for collagen synthesis

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52
Q

Structure of collagen

A

Amino acid sequence is part of a collagen chain
Every 3rd residue is Gly
Proline and hydroxyproline are also abundant - gly-pro-hyp is a frequent tripeptide

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53
Q

Structure of extracellular collagen

A

Contains 3 helical peptide chains, each nearly 1000 residues long
Stabilisation of this required hydroxyproline (which requires vit C for synthesis)
- required for inter-strand H bond formation - stabilisation

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54
Q

What is the most abundant protein in mammals

A

Collagen

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55
Q

Collagen is the main fibrous component of…

A

Skin, bone, cartilage, teeth

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56
Q

Proline hydroxylase

A

A dioxygenase enzyme
Takes part in addition of oxygen to 2 diff reactions; one is conversion of αKG to succinate, and second is conversion of proline to hydroxyproline
But first needs activation of oxygen

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57
Q

Hydroxylation of proline in collagen proteins - activation of oxygen

A

Requires Fe2+

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58
Q

Hydroxylation of proline in collagen proteins - conversion of αKG to succinate

A

In this process, Fe2+ is oxidised to Fe3+

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59
Q

Hydroxylation of proline in collagen proteins - Fe3+

A

Inhibits functioning of proline hydroxylase, so needs to be converted back to Fe2+
Vit C does this by donating e- to the Fe3+ –> Fe2+ so proline hydroxylase becomes active again –> can hydroxylate proline to make hydroxyproline

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60
Q

Hydroxylation of proline in collagen proteins - in this process, vitamin C itself is oxidised to…

A

Dehydroascorbate

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61
Q

Hydroxylation of proline in collagen proteins - if vitamin C isn’t present…

A

Proline hydroxylase will be inhibited by Fe3+, then proline won’t be converted to hydroxyproline –> collagen won’t have H bonds that stabilise its structure

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62
Q

Macrocytic anaemia: Megaloblastic anaemia - cause

A

One cause is lack of folate

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63
Q

What is folate required for

A

Synthesis of precursor molecules of DNA synthesis

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64
Q

Wills factor

A

A nutritional factor in yeast that prevents and cures macrocytic anaemia

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65
Q

Folic acid / folates (B9): Major structural components

A
  1. Bicyclic, heterocyclic, pteridine ring
  2. p-amino benzoic acid (PABA)
  3. Glutamic acid
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66
Q

Folic acid / folates (B9): Major structural components - pteridine ring

A

2 parts:
Pyrimidine
Pyrazine - modifications occur here

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67
Q

Do humans produce folic acid

A

No - we take it in by diet

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68
Q

Folic acid - active?

A

It’s a precursor molecule, so must be modified to make it into its active form (tetrahydrofolate)

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69
Q

Conversion of folic acid to tetrahydrofolate

A

2 successive reductions using NADPH –> NADP+

Folate –> dihydrofolate –> tetrahydrofolate

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70
Q

Conversion of folic acid to tetrahydrofolate - NADPH

A

The electron donor

i.e. reducing agent

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71
Q

Conversion of folic acid to tetrahydrofolate - catalysis

A

Both reduction reactions are catalysed by the NADPH-specific enzyme; dihydrofolate reductase (DHFR)

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72
Q

Glutamate - forms

A

Polyglutamate
Monoglutamate
(must be able to recognise!)

Addition of additional glutamic acid residues in liver cells yield a poly-γ-glutamate tail

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73
Q

Why is polyglutamate converted

A

It can’t be absorbed, so is converted to monoglutamate

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74
Q

Sources of folate

A

Bacteria, yeast and higher plants

In these sources, folates are polyglutamate form

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75
Q

Sources of folate - humans

A

Diet

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76
Q

Polyglutamate - intestine

A

In the intestine, polyglutamate is converted into monoglutamate form
Absorbed by active transport

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77
Q

Conversion of folic acid to tetrahydrofolate - where

A

Intestinal cells

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78
Q

Tetrahydrofolate - storage

A

Can be stored in liver (50% of THF in body)

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79
Q

Liver - glutamate form

A

Converted to polyglutamate

  • retains THF in liver cells
  • polyglutamate has higher affinity for enzymes
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80
Q

Folic acid: Major functional groups of 1C units

A

Methyl (CH3)
Methylene (CH2)
Formyl (HCO)

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81
Q

Coenzymes derived from folic acid (THF)

A

Participate in generation and utilisation of 1C functional groups

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82
Q

Folates are essential for…

A

Cell growth and tissue development

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83
Q

Folate must come from _______ in mammals

A

Exogenous sources

Because we can’t synthesise these derivates de novo

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84
Q

Folic acid: Where do the 1C units join

A

At the nitrogen 5 or nitrogen 10 position

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85
Q

Folic acid: Major sources of 1C units

A

Amino acids (serine)
Histidine
Glycine
Formate

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86
Q

Folic acid: Major end products of 1C metabolism

A

Methionine - involved in protein synthesis
dTMP - building block for DNA and RNA
Formyl-methionyl-tRNA - derivative of methionine, used by bacteria and mitochondria
Purines - building block for DNA and RNA

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87
Q

Antimetabolite

A

Synthetic compound
Usually structurally related to metabolite
Interferes with metabolite to which it’s related

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88
Q

Antimetabolite: Anticancer

A

Inhibit human DHFR

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89
Q

Antimetabolite: Antibacterial

A

Inhibit bacterial DHFR

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90
Q

Antimetabolite: Antiparasitic

A

Inhibit protozoa DHFR

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91
Q

Antimetabolite - cancer - how does it work

A

Reduce’s cells ability to proliferate by binding to the DHFR and inhibiting production of THF

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92
Q

Division of cancer cells

A

Divide faster than normal cells

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93
Q

Antimetabolite: Sulfanilamide and its derivatives

A

Competitively inhibit synthesis of folic acid –> decreases synthesis of nucleotides needed for replication of DNA

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94
Q

Antimetabolite: Methotrexate

A

Competitively inhibits DHFR

[Folic acid analogue is used to treat psoriasis, rheumatoid arthritis and neoplastic diseases]

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95
Q

Neural tube detects (NTDs) reflect…

A

A combination of genetic predisposition and environmental influences (folic acid)

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96
Q

Neural tube detects (NTDs) - how does this happen

A

Normally the CNS begins as a plate of cells which folds on itself to form a tube
Failure of closure results in NTDs

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97
Q

Neural tube detects (NTDs) - types

A 
2 main forms;
Anencephaly (main cranial defect)
Spina bifida (main caudal defect)
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98
Q

Neural tube detects (NTDs): Anencephaly

A

Cerebral cortex fails to develop
~1/3 of cases of NTDs
Invariability lethal - death either before or shortly after birth

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99
Q

Neural tube detects (NTDs): Spina bifida

A

Spinal cord develops abnormally
~2/3 of cases of NTDs
Causes paralysis of lower extremities and impaired bladder and bowel function
Not usually fatal unless accompanied by other conditions

100
Q

NTDs - prevention

A

Researchers found that 50-75% of NTDs can be prevented when women supplement their diet with folic acid

101
Q

NTDs: Methylation hypothesis

A

Proposed that folate deficiency causes NTDs due to decreased methylation of various molecules that are essential to cellular processes

102
Q

Vitamin A - synthesis in humans

A

Humans can’t synthesise vitamin A

103
Q

Vitamin A (retinol) - sources

A

Cartenoids, especially β-carotene in (often orange) plants

Esterified retinol from animal sources (originally sourced from carotenoids)

104
Q

Function of β-carotene in plants

A

Photosynthesis

Act as an accessory pigment - absorb light which is converted into chemical forms of energy

105
Q

β-carotene vs chlorophyll

A

Both undergo photosynthesis, but absorb light in a slightly diff wavelength to chlorophyll

106
Q

β-carotene: Conversion

A

Cleaved in intestine through middle –> 2x all-trans-retinal –> all trans-retinol –> all-trans-retinoic acid and 11-cis-retinal

107
Q

What form of vitamin A is transported around the body

A

All-trans-retinol

108
Q

What are the more active forms of vitamin A

A

All-trans-retinoic acid

11-cis-retinal

109
Q

Vitamin A: β-carotene - 11-cis-retinal

A

Role in vision

110
Q

Vitamin A: β-carotene - all-trans-retinoic acid

A

Hormone-like functions

  • binds to retinoic acid receptors (RAR)
  • regulates gene expression
  • development, immune function, reproduction
111
Q

Vitamin A: Retinyl ester

A

Hydrophobic

A form of vitamin A that travels around in chylomicrons and can be taken up by cells

112
Q

How do we store vitamin A

A

Retinyl ester is taken up by chylomicrons into the liver cells where it’s stored

113
Q

What happens to the stored vitamin A when we need it

A

Retinyl ester is converted into retinol, which is then transported around the body by retinol binding protein (RBP) –> binds to STRA6 and gets internalised

114
Q

Vitamin A transport: STRA6

A

A receptor in the cell membrane with a pore-like structure

115
Q

Vitamin A transport: STRA6 - steps

A

When RBP comes to a cell that expresses STRA6, it binds to it which transfers the retinol through the STRA6
Retinol then binds to other molecules to transfer through the hydrophilic area of cell

116
Q

Ways to transport vitamin A around the body

A

Lipid vesicles and RBP

  • storage and release
  • regulate peripheral levels of vit A
117
Q

Why do we need to regulate vitamin A in body

A

Don’t want to waste vitamin A

Can be toxic in excess

118
Q

Vitamin A - specificity

A

Receptor (STRA6) allows tissue specificity - regulates which tissues have access to vit A

119
Q

General concept - regulating molecules

A

Regulate in periphery (storage)
Regulate release by signals (change in environment or metabolic state)
Regulate transport of molecules
Regulate tissue specificity (receptors and channels)

120
Q

Vitamin A: Rhodopsin

A

11-cis-retinal combines with opsin via a lysine residue to form rhodopsin, which is a protein present in many rod cells within the eye

121
Q

Vitamin A: Rhodopsin - function

A

Converts light energy into a visual signal

122
Q

When does excessive vit A consumption occur

A

Typically occur when vitamin A is ingested in its preformed state (liver)
Doesn’t occur when ingesting carotenoids including β-carotene

123
Q

Hypervitaminosis A - symptoms

A

Acute: abdominal pain, nausea, vomiting, dizziness
Chronic: bone abnormalities, joint pain, visual disturbances, appetite loss, dizziness, peeling, oily/itchy skin, respiratory infection

124
Q

Vitamin D - dietary sources

A

Fish liver oils, fortified foods

supplements

125
Q

Rickets - symptoms

A

Bone pain
Dental deformities
Decreased muscle strength
Skeletal deformities, e.g. bowlegs, rib-cage

126
Q

Rickets - type of disease

A

Multi-factorial disease

127
Q

Which vitamin is a cholesterol derivative

A

Vitamin D

128
Q

How is vitamin D taken into our bodies

A

Can take in by diet, but most are made within our own cells

129
Q

Vitamin D - precursor molecule

A

7-dehydrocholesterol

130
Q

Synthesising vitamin D - steps

A

Dehydrocholesterol –UV–> previtamin D3 –> vitamin D3 –> liver: calcidiol –> kidneys: calcitriol

131
Q

What form of vitamin D is found within our bodies

A

Vitamin D3

132
Q

Vitamin D transport - steps

A

Previtamin D3 is hydrophobic, so is bound to VDBP (vitamin D binding protein) –> transported to liver then to kidneys (active form)

133
Q

Vitamin D: Active form - functions

A

2 diff ways; when it gets to cells, it binds to VDR (vitamin D receptor)

  • can function by activating pathways within cell (signal transduction)
  • more commonly, is involved in upregulation of a no of genes
134
Q

Vitamin D - functions

A

Bone: increases bone mineralisation
Intestine: increases absorption of Ca2+ and Pi
Immune cells: induces differentiation of immune cells

135
Q

Vitamin D: Bone mineralisation

A

The depositing of Ca2+ and phosphate ions in bones

136
Q

Vitamin D - excess

A

Can lead to disease if taken in excess

Where Ca2+ and phosphate become deposited in soft tissues instead of bones

137
Q

What is excess vitamin D due to

A

Due to taking too much vitamin D in supplementation

138
Q

Types of antibiotics (based on mode of action)

A

Bacteriocidal: Antibiotics that kill bacteria
- penicillin

Bacteriostatic: antibiotics that block growth

  • tetracyclines
  • sulphonamides
139
Q

Penicillin - history

A

First discovered by Ernest Duchesne, but was forgotten until Alexander Fleming rediscovered it

140
Q

What was the first true antibiotic

A

Penicillin

141
Q

What are most antibiotics in human use

A

Natural products, elaborated by one species of microbe (bacteria or fungi) as chemical weapons, often in times of crowding, to kill off other microbes in the neighbouring microenvironment

142
Q

What have many antibiotics been isolated from

A

Fungi (e.g. penicillins) and diff strains of filamentous bacterium (streptomyces)

143
Q

Antibiotics: Semi-synthetic modifications of total synthesis

A

Both produced newer generations of antibiotics

Semi = purify product from body and change it chemically

144
Q

Penicillin: Where did the fungus come from

A

Agar plates were open to environment and one spore of mould was transported from Freeman’s lab to Fleming’s lab
Agar plate left for 9 days, and penicillium excreted substances (‘mould juice’) which inhibited bacteria growth around it

145
Q

Penicillin: Temperature

A

Grows in temps below 20 degrees

146
Q

Staphylococcal: Temperature

A

Grows in temps around mid-20 degrees

147
Q

Penicillin can only affect…

A

New bacterial growth

148
Q

Who purified penicillin

A

Florey and Chain

149
Q

Penicillin: Florey’s breakthrough results - preliminary experiments

A

Dose of bacteria required to kill a mouse

150
Q

Penicillin: Florey’s breakthrough results - experiment

A

Peritoneal injections of bacterial culture into mice
After a period of time, they treated 2 groups of mice differently - untreated control (no penicillin) and treated mice (8 hourly injections for 4 days)

151
Q

Penicillin: Florey’s breakthrough results - experiment results

A

Treated mice: First 36 hours, quite sick (a few died)
As time progressed, had vastly improved health
After 48 hours, infected mice were indistinguishable from healthy mice

152
Q

Penicillin: Florey’s breakthrough results - experiment - control vs treated mice

A

Control: Within 2 days, all mice (24/24) were dead
Treated: A few died, but 21/24 survived

153
Q

Penicillin: Florey’s breakthrough results - high dosage

A

Other experiment showed that penicillin (even at a high dose) led to an advantage for mice (still a few survived)

154
Q

What does Penicillin come from

A

Comes from a fungus called penicillium

155
Q

Penicillium - structure

A

Looks like a paintbrush

156
Q

Penicillin: WWII

A

Hugely beneficial to treat wound pathogens such as Staphylococcus

157
Q

Penicillin: Following WII

A

Used in treatment of rheumatic fever and syphilis

158
Q

Penicillium: Food

A

Several species of Penicillium play a central role in production of cheese and various meat products

159
Q

Mechanism of antibiotic action: 5 antibacterial targets/pathways

A 
Inhibition of cell wall synthesis
Inhibition of protein synthesis
Inhibition of DNA or RNA synthesis
Inhibition of folate synthesis
Membrane disruption
160
Q

Gram -ve bacteria

A

Have an additional outer membrane - important because it can affect how some antibiotics get into the cell

161
Q

Penicillin: Inhibition of bacterial cell wall synthesis - steps

A
  1. Penicillin (or other inhibitor) is added to growth medium with a dividing bacterium
  2. Cell begins to grow, but is unable to synthesise new cell wall to accommodate the expanding cell
  3. As cellular growth continues, cytoplasm covered by PM begins to squeeze out through gap(s) in cell wall
  4. Cell continues to increase in size, but is unable to pinch off extra cytoplasmic material into 2 daughter cells
  5. Cell wall is shed entirely –> spheroplast, which is extremely vulnerable - prone to lysis
162
Q

Penicillin: Inhibition of bacterial cell wall synthesis - why is the bacterial cell unable to ‘pinch off’ extra cytoplasmic material into 2 daughter cells

A

Because formation of a division furrow depends on ability to synthesise new cell wall

163
Q

Penicillin: Inhibition of bacterial cell wall synthesis - what do you grow the bacteria in

A

In hypertonic solution - only allows cells that have a membrane around it to survive

164
Q

In presence of penicillin, bacteria seemed to die unless…

A

They were growing in a hypertonic solution

165
Q

Bacteria cells - structure

A

Surrounded by a protective envelope (cell wall)

166
Q

Bacteria cells: Cell wall - peptidoglycan

A

A structural macromolecule with a net-like composition - provides rigidity and support to outer cell wall
A polymer consisting of short chain amino acids the peptido portion carbohydrate backbone (glycan portion)

167
Q

Bacteria cells: Cell wall - peptidoglycan - how does it form the cell wall

A

A single peptidoglycan chain is cross-linked to other chains through the action of enzyme DD-transpeptidase (final step)

168
Q

DD-transpeptidase

A

An enzyme

AKA penicillin binding protein (PBP)

169
Q

Bacterial cell synthesis - steps (normal)

A

Transpeptidase cleaves off D-alanine and facilitates binding of other peptide chain to D-alanine –> cross-linked chains via covalent bonds - strengthens cell wall

170
Q

Bacterial cell synthesis - steps (penicillin)

A

Penicillin and D-Ala peptides have similar structure, so D-D-transpeptidase can’t tell them apart
Transpeptidase binds to penicillin and cleaves β-lactam ring –> forms an enzyme-penicillin complex which irreversibly binds to and inactivates transpeptidase

171
Q

Mechanism of antibiotic action: Inhibition of protein synthesis - example

A

Aminoglycosides - inhibit protein synthesis in bacteria

172
Q

Mechanism of antibiotic action: Inhibition of protein synthesis - how do they work

A

Bind to bacterial rRNA (30s subunit), disrupt ribosomal structure –> mistranslated proteins that can misfold –> cell death

173
Q

Mechanism of antibiotic action: Inhibition of protein synthesis - incorporation of misfolded membrane proteins into cell envelope can lead to…

A

Increased drug uptake by allowing more drugs to enter the membrane

174
Q

Mechanism of antibiotic action: Inhibition of DNA or RNA synthesis - example

A

Rifamycin class of antibiotics (e.g. rifampicin)

175
Q

Mechanism of antibiotic action: Inhibition of DNA or RNA synthesis - how do they work

A

Bind to actively transcribing RNA polymerase –> inhibits production of RNA

176
Q

Mechanism of antibiotic action: Inhibition of folate synthesis (antimetabolites) - example

A

Sulfonamides - antibiotics that inhibit a bacteria-specific reaction

177
Q

Mechanism of antibiotic action: Inhibition of folate synthesis (antimetabolites) - sulfonamides

A

Competitively inhibit dihydropteroate synthetase (enzyme involved in synthesis of folic acid)

178
Q

Peptidoglycan cell walls - humans

A

Not present in humans

179
Q

Mechanism of antibiotic action: What’s the most recent target of widespread clinical utility

A

Membrane disruption

180
Q

Mechanism of antibiotic action: Membrane disruption - example

A

Lipopeptide antibiotics, e.g. daptomycin

181
Q

Mechanism of antibiotic action: Membrane disruption - structure

A

A peptide sequence to which a fatty acid moiety is covalently attached
Huge lipo group and a peptide group

182
Q

Mechanism of antibiotic action: Membrane disruption - how does it work

A

Mechanism of action unclear

Likely to include insertion into membrane –> membrane disruption and loss of MP and lysing of cell

183
Q

Classes of AB-resistant pathogens that are a medical concern

A

MRSA - methicillin-resistant staphylococcus aureus
Drug-resistant gram -ve bacteria
Drug-resistant mycobacterium tuberculosis

184
Q

Classes of AB-resistant pathogens that are a medical concern: MRSA

A

80% of staph are resistant to penicillin

Methicillin was designed to overcome penicillin

185
Q

Classes of AB-resistant pathogens that are a medical concern: Drug-resistant gram -ve bacteria

A

e.g. Kirebsiella pneumoniae

Additional outer membrane - restricts type of antibiotics we can use

186
Q

Classes of AB-resistant pathogens that are a medical concern: TB

A

TB can develop many resistances

187
Q

What’s driving the development of drug resistance

A

Increased use of antibiotics –> increased level of resistance
Human: 1.4M kg/yr, about 1/2 inappropriately prescribed
Food animals: often fed antibiotics as part of food source; ~14M kg/year

188
Q

Where does resistance to AB come from

A

Inherent / natural resistance

Acquired resistance

189
Q

AB-resistance: Inherent/natural resistance

A

Natural/physical characteristics

Pre-determined natural things the bacteria already has, e.g. gram -ve bacteria have additional membrane

190
Q

AB-resistance: Acquired resistance

A

Bacteria that were previously susceptible are now resistant

Resistance developing in a sub-pop or strains of bacteria

191
Q

Acquired bacterial resistance - types

A

Vertical gene transfer

Horizontal gene transfer

192
Q

Acquired bacterial resistance: Vertical gene transfer

A

Transfer of spontaneous resistance gene mutations in bacterial chromosome to bacterial progeny during DNA replication
i.e. parent to progeny

193
Q

Acquired bacterial resistance: Vertical gene transfer - commonality

A

Mutation is a v rare event, but v fast growth of bacteria and absolute no of cells attained means it doesn’t take long before resistance develop
Spontaneous mutation frequency for antibiotic resistance is ~10^-8 or -9

194
Q

Acquired bacterial resistance: Vertical gene transfer - Darwinian evolution

A

Process is driven by natural selection
In the selective environment of the antibiotic, the wild-type are killed and resistant mutant is allows to grow and flourish

195
Q

Acquired bacterial resistance: Horizontal gene transfer

A

Genetic material contained in small packets of DNA can be transferred between individual bacteria of same or diff species

196
Q

Acquired bacterial resistance: Horizontal gene transfer - mechanisms

A

Conjugation
Transduction
Transformation

197
Q

Plasmid

A

Small circular piece of DNA
Generally confers an advantage to the bacteria
Passed down to their progeny

198
Q

What is thought to be the main mechanism of horizontal gene transfer

A

Conjugation

199
Q

Acquired bacterial resistance: Horizontal gene transfer - conjugation

A

Transmission of resistance genes following direct contact between 2 bacteria via pilus (bridge)

200
Q

Plasmids - conjugation

A

Plasmids are key players in conjugation exchange

Located in cytoplasm of donor and recipient cell, and exchange through the pilus

201
Q

Acquired bacterial resistance: Horizontal gene transfer - what does conjugation allow

A

Allows resistance to spread among a pop of bacterial cells much faster than simple mutation and vertical gene transfer would permit

202
Q

Acquired bacterial resistance: Horizontal gene transfer - transduction

A

Antibiotic resistance genes are transferred between 2 closely related bacteria by bacteria-specific viruses (bacteriophages)
Resistance genes generally integrated into chromosome of recipient cell

203
Q

Acquired bacterial resistance: Horizontal gene transfer - what does transduction require

A

A virus (bacteriophage), which picks up a resistance gene in one bacteria and transfers it into a recipient cell

204
Q

Acquired bacterial resistance: Horizontal gene transfer - transformation

A

Occurs when naked DNA is released into the external environment, normally due to death and lysis of an organism and is taken up by another bacterium
Antibiotic-resistance can be integrated into chromosome or plasmid of recipient cell

205
Q

Principal resistance mechanisms for bacterial survival

A

Efflux pumps
Enzymatic degradation of antibiotic
Enzymatic modification of antibiotic

206
Q

Principal resistance mechanisms for bacterial survival: Efflux pump

A

Pumps antibiotics back out of bacterial cells through efflux pump proteins to keep intracellular drug conc below therapeutic levels
Pumps are variants of membrane pumps possessed by all bacteria to move molecules in and out of cells

207
Q

For antibiotics to be effective…

A

They must reach their specific bacterial targets and act in a reasonable timeframe

208
Q

Principal resistance mechanisms for bacterial survival: Efflux pumps - example

A

Resistance to tetracyclines (aminoglycosides) - conc too low to block protein synthesis because when they come into the cell, they’re quickly pumped back out

209
Q

Principal resistance mechanisms for bacterial survival: What do efflux pumps prevent

A

Prevents antibiotic from interacting with target inside cell

210
Q

Principal resistance mechanisms for bacterial survival: Enzymatic degradation of antibiotic

A

Antibiotic is destroyed by chemical modification by enzyme that’s elaborated by resistant bacteria
e.g. penicillin

211
Q

Principal resistance mechanisms for bacterial survival: Enzymatic degradation of antibiotic - Penicillin

A

Deactivation of β-lactam in penicillin by expression of β-lactamase by resistant bacteria
Lactamase-producing bacteria secrete the enzyme into the periplasm to destroy β-lactam ring in antibiotics before they can reach their targets

212
Q

β-lactamase

A

A hydrolytic enzyme
AKA penicillinase
Expressed by resistant bacteria

213
Q

Principal resistance mechanisms for bacterial survival: Enzymatic degradation of antibiotic - How many penicillin molecules can be hydrolysed

A

A single β-lactamase can hydrolyse 1000 penicillin molecules per second - very effective

214
Q

Why was methicillin designed

A

It’s a second generation semi-synthetic derivative of penicillin, designed to be resistant to β-lactamase cleavage

215
Q

Principal resistance mechanisms for bacterial survival: Enzymatic modification of antibiotic

A

Antibiotic is modified by an enzyme so it’s no longer effective

216
Q

Principal resistance mechanisms for bacterial survival: Enzymatic modification of antibiotic - resistance enzymes

A

Acetyl transferases

Phosphoryl transferases

217
Q

Principal resistance mechanisms for bacterial survival: Enzymatic modification of antibiotic - example

A

Antibiotic chloramphenicol can be enzymatically inactivated by addition of acetyl or phosphate groups
These modifications decorate the periphery of the antibiotic and interrupt binding to ribosomes - physical barrier

218
Q

Transferases

A

Transfer a group onto a molecule

219
Q

Other resistance mechanisms: MRSA

A

Release fatty decoys (vesicles)
Daptomycin binds to inserts into these vesicles rather than going into bacterial cell
Decreases amount of daptomycin getting into bacterial cell

220
Q

Universal provision of antibiotics could prevent ___ of deaths from pneumonia

A

75%

221
Q

Innovation gap

A

Between 1962 and 2000, no major classes of antibiotics were introduced

222
Q

Ideal antibiotic - characteristics

A

Kills/inhibits growth of harmful bacteria but doesn’t affect beneficial bacteria
Able to act regardless of site of infection
Exceptional blood/fluid circulation
Broad spectrum
Large therapeutic window
Modifiable / not able to lead to resistance

223
Q

Ideal antibiotic: Exceptional blood/fluid circulation

A

Ability to travel well in blood and fluids of body and able to access all infections

224
Q

Ideal antibiotic: ADME

A

Easily Absorbed, Distributed, well Metabolised and easily Excreted

225
Q

Ideal antibiotic: Broad spectrum

A

Ideally treat all bacteria at once

226
Q

Ideal antibiotic: Large therapeutic window

A

A window over which each drug works where it’s safe dose is effective

227
Q

Does the ideal antibiotic exist

A

No - but the ability to modify antibiotics is useful

228
Q

What is clavulanic acid

A

β-lactamase inhibitor

229
Q

Clavulanic acid - how does it work

A

Lacks antibiotic activity but irreversibly binds to β-lactamase to prevent it from hydrolysing β-lactam antibiotics (e.g. penicillin and amoxicillin)

230
Q

Clavulanic acid - structure

A

Looks similar to penicillin

231
Q

Clavulanic acid - what is it used with

A

Used in combination with antibiotics - soaks up β-lactamase so the antibiotic can function to inhibit bacterial cell wall synthesis

232
Q

Strategies to overcome resistance: Approaches to develop new antibiotics

A

Modification of common core structures of diff antibiotic classes using medicinal chemistry
Identification of new antibiotic scaffolds through searches of underexplored ecological niches and bacterial taxa
Bioinformatic analysis of bacterial genomes

233
Q

Strategies to overcome resistance: Modification of common core structures

A

Scaffold alterations; two strategies:

  1. Tetracycline scaffold can be chemically modified –> tetracycline derivative (e.g. tigecycline) that’s no longer a substrate for the efflux pump
  2. A new scaffold (e.g. retapamulin) which isn’t a substrate for efflux and binds to a diff site in ribosome can be used instead of tetracycline
234
Q

Strategies to overcome resistance: Modification of common core structures - synthetic tailoring

A

Where the new generation only looks slightly diff - just enough for the bacterial resistance gene to no longer recognise it

235
Q

Strategies to overcome resistance: Modification of common core structures - characteristics of a new antibiotic which would be good for synthetic scaffolds

A

Active against gram +ve and -ve pathogens
Lack of cross-resistance to existing drugs
Able to be synthetically tailored

236
Q

Strategies to overcome resistance: Identification of new antibiotic scaffolds

A

More than 2/3 of clinically used antibiotics are natural products or semisynthetic derivatives

237
Q

Strategies to overcome resistance: Identification of new antibiotic scaffolds - examples

A

Komodo dragons live in bacterial-infested waters
Marine life
Plant defenses
Antibiotic-contaminated lake

238
Q

Strategies to overcome resistance: Bioinformatic analysis of bacterial genomes

A

Genome sequences of bacteria and fungi have up to 2 dozen silent clusters for natural product biosynthesis
Approaches used to turn on silent biosynthetic gene clusters to evaluate the activity of resultant small molecules

239
Q

Strategies to overcome resistance: AMPs and lipopeptides

A

Insert into bacterial membrane –> physically damages bacterial morphology

240
Q

AMPs

A

Antimicrobial peptides

241
Q

Strategies to overcome resistance: AMPs and lipopeptides - disadvantage

A

Limited medical use - break down easily in body, so it’s hard to get them delivered to target without having them destroyed on the way

242
Q

Strategies to overcome resistance: AMPs and lipopeptides - nanoparticles

A

Potentially nanoparticles made of AMP-like peptides could enhance their activity due to multivalent interactions
More stable

243
Q

Strategies to overcome resistance: AMPs and lipopeptides - SNAPPs

A

Structurally nanoengineered antimicrobial peptide polymers

244
Q

Strategies to overcome resistance: AMPs and lipopeptides - SNAPPs - how does it work

A

Proceeds via a multimodal mechanism of bacterial cell death by:

  • outer membrane destabilisation (gram -ve)
  • unregulated ion movement across cytoplasmic membrane (change in ion efflux)
  • induction of apoptotic-like death pathway
245
Q

Strategies to overcome resistance: AMPs and lipopeptides - why is multimodal mechanism importan

A

Bacteria will find it harder to overcome all 3 types of death induction

BIOSCI 106 (6 decks)

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