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MBB 328 > Lecture 19B - Antibiotics B > Flashcards

Lecture 19B - Antibiotics B Flashcards

1
Q

What is tetrahydrofolate (THF)?

A 
Cofactor essential for synthesis of
precursors of DNA, RNA, protein,
fatty acids and vitamins in bacteria
and humans, and for
N-formylmethionine (fMet) in
bacteria (initiation of protein
synthesis)
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2
Q

Precursor for THF?

A

dihydrofolic acid (DHF)

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3
Q

Precursor for DHF?

A

p-aminebenzoic acid (PABA)

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4
Q

Enzymes that convert PABA to DHF?

A

Pteridine synthetase and DHF synthetase

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5
Q

What is the difference in how bacteria synthesize DHF compared to mammals?

A

Mammalian cells use Folic Acid (Folate) obtained from food while bacteria synthesize it from PABA -> dihydropteroic acid -> DHF

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6
Q

What do sulfonamides target?

A

Structurally similar to
PABA – they are competitive
inhibitors of pteridine synthase in
bacteria

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7
Q

What do trimethoprim target?

A 
Structurally similar
to DHF – it acts as a competitive
inhibitor of the microbial DHF
reductase but not the mammalian
enzyme
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8
Q

How does resistance develop against sulfonamides?

A

Mutation in pteridine synthetase such that it no longer binds but is still functional (immunity), some bacteria can make THF directly from folic acid like mammals (bypass)

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9
Q

How does resistance develop against trimethoprim?

A

Mutation in DHF reductase such that it no longer binds but is still functional (immunity), acquisition of a plasmid-encoded DHF reductase that doesn’t bind trimethoprim (bypass)

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10
Q

How does metronidazole work?

A

damages DNA, inhibits DNA

synthesis

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11
Q

How is metronidazole activated?

A

By bacterial
housekeeping proteins flavodoxin
and ferredoxin in microaerophilic
and obligate anaerobes

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12
Q

Why is metronidazole only activated in bacterial cells?

A

Lack flavodoxin and ferredoxin

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13
Q

Which bacteria is metronidazole used for?

A

Helicobacter pylori and Clostridium difficile, also effective against some eukaryotic pathogens that can activate metronidazole

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14
Q

Which bacteria are sulfonamides and trimethoprim used for?

A

Many species - broad spectrum

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15
Q

How does resistance develop against metronidazole?

A

Upregulation of DNA repair enzymes (RecA) (bypass/immunity)

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16
Q

How do quinolones and fluoroquinolones work?

A

Inhibit DNA replication, quinolones bind to and stabilize the gyrase:DNA complex in DNA gyrase and prevent strand resealing, resulting in double strand breaks in the DNA.

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17
Q

What do quinolones/fluoroquinolones target?

A

DNA gyrase (Topoisomerase II)

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18
Q

Difference between quinolones and fluoroquinolones?

A

Fluoroquinolones are just fluorinated, more active and effective quinolones

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19
Q

Which bacteria is ciproflaxin(quinolone) used for?

A

B anthracis (anthrax)

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20
Q

How is resistance developed against quinolones/fluoroquinolones?

A

Single mutation in DNA gyrase can make bacteria resistant - gyrase still active but no longer binds (immunity)

21
Q

What does rifampicin target?

A

Exit channel on RNA polymerase beta subunit

22
Q

How does rifampicin work?

A

Blocks emergence of new RNA from exit channel in bacterial RNA pol beta subunit

23
Q

How is resistance developed against rifampicin?

A

Single mutation in
RNA polymerase that prevents rifampin binding
but not RNA polymerization.

24
Q

What do aminoglycosides like streptomycin target?

A

Bind to the bacterial ribosomal 30S subunit, inhibit the initiation and
elongation steps in protein synthesis. Allows the wrong tRNA to bind inhibiting protein synthesis.

25
Q

How does resistance develop against aminoglycosides?

A

Aminoglycosidal modifying enzymes - modification reduces their transport into cell (too big) and their ability to bind to the 30S subunit

26
Q

What do tetracycline target?

A

Bind to the 30S subunit and inhibits tRNA binding at the A site

27
Q

How does tetracycline work?

A

Distort A site and prevent alignment of
aminoacylated tRNA with codon on mRNA –
block peptide synthesis

28
Q

How is resistance developed against tetracycline?

A

Efflux pumps, modification by tetracycline enzymes, cytoplasmic proteins that protect 30S subunit by preventing binding without disrupting protein synthesis

29
Q

What do chloramphenicol target?

A

Binds to the peptidyl transferase on the 50S subunit, inhibits the peptidyl transfer step in protein synthesis

30
Q

How is resistance to chloramphenicol developed?

A

Bacteria
have/acquire an enzyme, chloramphenicol
acetyltransferase, which acetylates chloramphenicol,
inactivating it.

31
Q

What do macrolides target?

A

Bind to the 50S subunit and inhibit

translocation

32
Q

What is azithromycin? What is it used for?

A

Macrolide. Very effective at treating
sexually transmitted infections such as
Chlamydia and N. gonorrhoeae – single
dose (cf. a full course) but very expensive

33
Q

How is resistance against macrolides developed?

A

Efflux pump

34
Q

What is the difference between lincosamides/streptogramins and macrolides?

A

Differ in structure from macrolides but have the same mechanism - bind to roughly the same site on the 50S ribosome and inhibit translocation step. Lincosamides kill intestinal microbiota, associated with C difficile infections. Streptogramins used in agriculture - many resistance strains.

35
Q

Which antibiotics are used against 30S subunit of bacterial ribosome? 50S subunit?

A

30S - Tetracycline, aminoglycosides

50S - Chloramphenicol, macrolides, streptogramins, lincosamides

36
Q

What does teixobactin target?

A

Binds to precursors of peptidoglycan – Lipid II and Lipid II precursors and prevents PBP/transpeptidase activity, blocking peptidoglycan synthesis

37
Q

Which bacteria is teixobactin effective against?

A

Gram-positive bacteria – S. aureus, S. pneumoniae, M. tuberculosis,
vancomycin-resistant enterococci (VRE, have D-Ala-D-Lac but can still bind teixobactin). Gram-negatives are resistant

38
Q

How are gram-negatives resistant to teixobactin?

A

Act on PG and WTA in gram-positive bacteria which lack OM - presence of the outer membrane prevents uptake of teixobactin

39
Q

Why is resistance less likely to occur with teixobactin?

A

Acts on lipid II, a non-protein molecule - can’t change lipid II

40
Q

What kinds of organisms can be found in the microbiota?

A

Bacteria, archaea, fungi, some protozoa and viruses/phages

41
Q

Why are most microbes found in the gut?

A

Provides stable nutrients and temperature

42
Q

Difference between microbiota and microbiome?

A

Microbiota - refers to the community microbes

Microbiome - refers to the combined genomes

43
Q

How are the 60-90% non-culturable gut microbiota identified?

A

(1) targeted sequencing of phylogenetically
informative genes, usually 16s rRNA, a taxonomic marker for bacteria, or (2) by random sequencing of
all genes in the microbial community (shotgun metagenomic sequencing of stool samples). Successful identification of bacterial species in a microbiome requires a match with existing genome
sequences in databases

44
Q

Which bacteria dominate in the gut?

A

In adults, Gram-positive Firmicutes (eg.
Clostridia, Lactobacilli, Entercocci) and Gramnegative
Bacteroidetes dominate.
Most gut bacteria are anaerobic. Some are
adherent, most are in the lumen of the colon
(large intestine).

45
Q

What are the metabolic functions of gut microbiota?

A

Aid in digestion by fermenting/breakdown of complex carbohydrates, amino acids, bile salts, lipids,
fatty acids, salvage urea, synthesize essential amino acids, vitamins (eg. vitamin K, folic acid) – these nutrients are used by the bacteria but are also available to host, modulate appetite, etc

46
Q

What are the trophic functions of gut microbiota?

A

Facilitate gut development by controlling epithelial cell proliferation and differentiation; influence organ development, development of lymphatic tissues, angiogenesis, fat storage

47
Q

What are the protective functions of gut microbiota?

A

Protective: out-compete pathogenic bacteria for nutrients, prevent colonization by pathogens,
stimulate the immune system, facilitate its maturation to eliminate pathogens but tolerate
commensals

48
Q

How do C difficile infections occur?

A

May be present in the gut in low levels prior
to antibiotic treatment, but controlled by competition with commensal bacteria, or may be acquired
by ingestion of spores in hospital. C. difficile spores are robust and difficult to kill – are prevalent in
hospital settings.

49
Q

What is C difficile?

A

Anaerobic spore-forming Gram-positive bacillus. Causes severe diarrhea, pseudomembranous colitis, toxic
megacolon - can be fatal. Resistant to multiple antibiotics. Vegetative cells produce toxins TcdA, TcdB
(for Toxin C. difficile A, B) that cause epithelial damage. Levels of glucose and other nutrients affect expression of C. difficile genes. Intestinal components such as bile acids induce C. difficile spores to germinate.

MBB 328 (10 decks)

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