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PHAR 510 > Lecture 9 - Adjuvants and Alternatives to Antibiotics > Flashcards

Lecture 9 - Adjuvants and Alternatives to Antibiotics Flashcards

1
Q

4 ways to find new antibacterials

A
  1. better screening to find new antibiotics
  2. better antibiotics (hybrid)
  3. better adjuvants
  4. alternatives to antibiotics
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2
Q

what is Cefiderocol used for?

A

kept as a reserve antibiotic, only used when needed –> not used as first-line

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3
Q

describe use of nasal microbiota as source of new antibiotics

A

nasal microbiota can prevent pathogen growth

use nasal microbiome bacteria S. lugdunensis as antibiotic that stopped growth of S. aureus

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4
Q

describe use of soil bacteria as source of new antibiotics

A

use multichannel microchip that can be put in soil and allow bacteria to be isolated but still receive natural nutrients –> get large + diverse pool of bacteria

identified TEIXOBACTIN –> less antibacterial resistance

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5
Q

what are antibiotic conjugates/hybrids?

A

antibiotics joined together or joined with another moiety

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6
Q

what is CEFIDEROCOL?

A

siderophore conjugated with cephalosporin (beta-lactam)

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7
Q

role of siderophore in cefiderocol?

A

pathogen recognizes siderophore and wants to get iron from it, but then bacteria will end up taking up the antibiotic and accumulate in periplasm

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8
Q

what type of bacteria does cefiderocol act on?

A

gram negative

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9
Q

what are most antibiotic adjuvants?

A

most are anti-resistance agents

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10
Q

5 examples of anti-resistance agents

A
  1. beta-lactamase inhibitors
  2. aminoglycoside-inactivating enzyme inhibitors
  3. efflux pump inhibitors
  4. out membrane permeabilizers
  5. anti-biolfilm agents
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11
Q

role of anti-biofilm agents?

A

causes dispersal of biofilm or inhibits biofilm formation

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12
Q

what are beta-lactams typically administered with?

A

beta-lactam antibiotic + beta-lactamase inhibitor combo

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13
Q

are beta-lactamase inhibitors active against all beta-lactamases?

A

no, classes B/C/D are hardest to target

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14
Q

what type of beta-lactamases are we not able to target?

A

Class B –> metallo-B-lactamase

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15
Q

what is a metallo-B-lactamase?

A

has Zn atom in active site and gives resistance to all beta lactams

resistance gene found on plasmid containing other resistance genes

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16
Q

how were metallo-B-lactamases first detected?

A

in bacterial species with low pathogenic potential

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17
Q

what is an improved way to use beta-lactamase inhibitors?

A

make them beta-lactamase inhibitors AND antibiotics on their own (block PBP) –> more efficient, less resistance, better against ESKAPE pathogens

18
Q

2 examples of non-traditional antibacterial agents

A
  1. microbiome-modulating agents
  2. inactivating toxins produced by bacteria
19
Q

what is a host-derived approach?

A

stimulate the immune system

20
Q

what are anti-virulence strategies?

A

target virulence factors

21
Q

4 anti-virulence strategies

A
  1. secretion system
  2. adhesins
  3. bacterial toxin
  4. quorum sensing
22
Q

why is it good to target virulence factors of bacteria?

A

pathogenesis is mediated by many adhesions and secreted molecules that allow for adhesion and modulate/disrupt host cells

23
Q

5 benefits of anti-virulence strategy

A
  1. targeting virulence factor = not putting selective pressure = less resistance
  2. virulence factors limited to 1 pathogen = specific and selective approach
  3. quick
  4. doesn’t need immunocompetent patient
  5. easier to target extracellular/secreted things instead of penetrating cell
24
Q

what is needed in addition to anti-virulence strategy ?

A

must have a way to clear infection and good diagnostics

25
Q

why are anti-virulence strategies quick?

A

inactivating virulence factor = inhibiting pathogenicity

26
Q

4 downsides of anti-virulence factors

A
  1. must be mechanism to clear infection
  2. must have definite knowledge of pathogen (good diagnostics)
  3. pathogenesis may involve many virulence factors, 1 might not be enough
  4. may not be effective in all forms of disease by the same pathogen
27
Q

what are AB toxins?

A

A = Activity domain –> enzymatic domain that must enter cell to allow bacteria to infect

B = Binding domain –> binds receptor on cell and forms pore so A can enter

28
Q

3 current ways to target AB toxins

A
  1. Ab
  2. vaccine
  3. small molecules
29
Q

when did targeting bacterial toxins begin?

A

in late 1800s with diphtheria antitoxin serum

30
Q

what are toxoids?

A

chemically inactivated toxin that causes no damage but is still recognizable by immune system

31
Q

what type of vaccines are the Diphtheria and tetanus vaccines?

A

toxoid vaccines

32
Q

what is the cholera vaccine?

A

cholera toxin B

33
Q

what is Bezlotoxumab used for?

A

C. diff infection

34
Q

how does Bezlotoxumab work?

A

Ab that recognizes toxin B of C. diff and reduces recurrent C. diff infection

35
Q

testing Bezlotoxumab against toxin A and B of C. diff

A

only worked on Toxin B

36
Q

Issue with using antibodies to target C. diff

A

toxins produced by C. diff are made in the gut lumen and stay localized there

therefore, must have enough Ab cross the epithelium and enter mucosal environment to be able to have an effect

37
Q

how can we improve the use of antibodies for C. diff?

A

Oral Ab so they are in the gut lumen with the toxins

38
Q

describe the development of oral antibodies for C. diff

A

immunized pregnant cows to make hyperimmune bovine colostrum with Ab that target C. diff spores, vegetative cells, and toxin B

39
Q

describe the development of small molecule drug for C. diff

A

inactivate toxin B with auto-proteolysis induced by small molecule

40
Q

describe pore-forming toxins and 2 examples

A

toxins that oligomerize to form big pores

  1. a-hemolysin from S. aureus
  2. pneumolysin from S. pneumoniae
41
Q

describe the use of liposomes to target pore-forming toxins

A

make liposomes that are hospitable for the toxin so it can soak up the toxin rather than the cells taking the toxin

42
Q

issue with liposome for pore-forming toxin

A

hard to have affinity of lipososome for toxin that competes with cells

PHAR 510 (11 decks)

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