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mimm 465 > Lecture 5: antibiotic resistance > Flashcards

Lecture 5: antibiotic resistance Flashcards

1
Q

What are antibiotics

A

compounds that can kill or inhibit the growth of the bacteria

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2
Q

how was the antibiotics found

A

-found to be produced by mold aka penicilium

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3
Q

true or false: antibiotiocs can be synthetic or natureal

A

truewhat are the

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4
Q

what are the main routes of administration for antibioticvs

A

oral or intraveinous

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5
Q

what makes a drug antibacterial

A

-spectrum of activirty: gram + vs _ and aerobes vs anaerobes, specific sopecies
-bacteriostatic vs bactericidal
-mechanism of action, drug target
-pharmacology: potency, delivery and side effects

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6
Q

what does bacteriostatic mean

A

-interferes with a process required for cell replication (ex: protein synthesis) causing an arrest in growth

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7
Q

what does bactericidal mean

A

-interferes with a process required for cell survival (ex: lysis of cell wall, dna damage etc) causing cell death

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8
Q

cell wall synthesis inhibiotors

A

-b lactams and glycopeptide abx mechanisms
-binds d-ala-d-ala terminal
-structure is similar do d-ala-d-ala terminal portion
-bind to PBPactive domain (penicilin binding proteins)

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9
Q

True or false: cell wall synthesis is conserved across many species and has multiple steps that can be inhiboted by different types of compound

A

true

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10
Q

many cell wall synthesis inhibitors are not active against….

A

gram - bacteria because they can’t penetrate the outer membrane

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11
Q

what makes beta lactams easy to differenciate

A

they have a common beta lactam ring

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12
Q

true or false: all beta lactams are all the same

A

nah different classes of beta lactams with different susceptibility to bete lactamase degredation and spectrum of activity

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13
Q

true or false: resistance is increasing but newer generations are hydrolyzed by certain beta lactamases

A

false; they are not hydrolyzed

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14
Q

what is the mechanism of resistance of the beta lactams

A

-hydrolysis of beta lactamase
-expression of alternate PBP with low binding affinity

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15
Q

name protein synthesis inhibitors

A

-chloramphenicol
-macrolides, clindamycin and streotogramins
-aminoglycosides
-tetracyclines
-linezolid

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16
Q

all protein synthesis inhibitors, except for…. are bacteriostatic

A

aminoglycosides

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17
Q

what inhibits peptidyl transferase centre (50S inhibitor)

A

chloramphenicol

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18
Q

what inhibits peptide exit tunnel (50S inhibitor)

A

mecrolides

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19
Q

what inhibits trna delivery (30S inhibitor)

A

tetracyclines

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20
Q

what inhibits trna translocation (30S inhibitor)

A

aminoglycosides

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21
Q

what is the mechanism of action and antibiotic resistance of protein synthesis

A

-expression of aminoglycosides modifying enzymes (acetylation, phosphorylation)
-modification of ribosomal
-reduced uptake/permeability

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22
Q

aminoglycosides structure:

A

-structurally varied with natural and semi synthetic compound with a central aminocyclitol ring
-with numerous hydroxyl and amine group

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23
Q

aminoglycosides: broad spectrum with ……

A

excellent activity against gra, - and some gram +

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24
Q

clinical use of aminoglycosides

A

-no oral drug
-has significant systemic toxiciyu
-usually used for multi drug resistant or severe gram - infections or topical use

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25
Q

mechanism of action of aminoglycosides

A
  • Binding to 30S ribosomal subunit, inhibits protein translation at the translocation reaction and prevent the subunit splitting
  • Induce mistranslation by stabilizing the binding of non cognate tRNA to the mRNA; Mistranslation of membrane proteins likely indirectly causes loss of cell-wall integrity
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26
Q

what are antibiotics that target nucleic acid synthesis

A

-dna gyrase: quinolones
-rna polymerase: rifampin

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27
Q

what is the spectrum pf action in quilonoles

A

-bactericidal drug with broad spectrum with activity against gram + and - bacteria, mycobacteria

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28
Q

is quinolones natural

A

-synthetic drug but derived from natural compounds

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29
Q

are quilonoles well tolerated?

A
  • Highly effective and well tolerated treatment and widely used for a wide range of human infections (e.g. GI, urinary, respiratory infections), even Mycobacteria (including TB)
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30
Q

why is there resistance with fluoro quinolones

A

due to widespread use

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31
Q

mechanism of action of quinolones

A
  • Inhibits bacterial gyrase and Topoisomerase IV, which relaxes DNA supercoils
  • Causes DNA fragmentation due to residual nuclease activity
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32
Q

mechanism of resistance in quinolones

A

Mechanisms of resistance
* point mutation of binding site
* efflux pumps
* porin expression and membrane permeability

33
Q

mechanism of action of rifampin

A

Rifampin inhibits transcription by binding to the β subunit (encoded by the rpoB gene) of the prokaryotic RNA polymerase (RNAP) which facilitate the direct blocking of the elongating RNA.

34
Q

mechanism of resistance with rifampin

A

point mutations of binding site

35
Q

hiw to assess antibiotic susceptibility

A

Conventionally defined by growth at high drug concentration by MIC (Minimal Inhibitory Concentration), zone of inhibition or E-test

36
Q

resistance to multiple compounds=…

A

multidrug resistance

37
Q

The outer membrane of Gram negative bacteria and mycobacterial cell wall are highly……

A

hydrophobic and impermeable and acts as a selective barrier.

38
Q

hydrophilic molecules and some hydrophobic molecules must enter through…..

A

size limited pores

39
Q

low permeability account for resistance to drugs such as…

A
  • Low permeability account for resistance to drugs such as beta lactams, glycopeptides (vancomycin) in gram-negatives
  • Typically responsible for intrinsic resistance but can also be acquired through differential expression or mutations of certain porins.
40
Q

Antibiotic resistance due to drug efflux

A
  • Antibiotics are pumped out of the cell (outer and inner membrane) and therefore cannot reach their targets
  • Major mechanism in gram negative bacteria
  • Complex “multi-purpose” efflux pumps
  • Can cause multi-drug resistance
41
Q

which type of pump resists to multipledrugs

A

acrb (rnd family) and lmrA (ABC superfamily)

42
Q

Antibiotic resistance due to target mutation

A
  • Can be due to genetic mutation of the target gene
  • Example: gyrB (gyrase) mutations reduce the binding affinity of quinolones to GyrA and confer quinolone resistance
  • Can be due to enzymatic modification of the target structure
  • Erm genes which encore methyl transferases that can modify of 50S subunit and confer macrolide resistance
43
Q

name beta lactams

A

-penicilins
-monobactam
-cephalosporins
-carbapene,

44
Q

enzymes secreted in… are highly effective at cleaving beta lactam rings

A

periplasm

45
Q

Different beta-lactamases exist with different spectrum… now there are extended

A

spectrum (ESBL) that can cleave cephalosporins and metallo-beta lactamases (MBL) that cleave carbapenems.

46
Q

where are esbl and mbls are encoded

A

Encoded on plasmids (acquired resistance) or on the chromosome of some gramnegative bacteria (eg. intrinsic resistance in Pseudomonas).

47
Q

Aminoglycoside modification

A

-This inactivation of antibiotics depends on the modifying enzymes’ function, i.e., the addition of chemical groups to vulnerable sites of the antibiotic molecule or antibiotic targets.
* Various different chemical groups can be transferred, including acyl, phosphate, nucleotidyl, ribitoyl, glycosyl , and thiol groups.
* This prevents proper binding of aminoglycosides to the 30S subuni

48
Q

what does intrinsic resistance

A

Intrinsic resistance: resistance to an antimicrobial is inherent to a bacterial
species ( “natural resistance”)
-ex: absence of target
-low permeability
-low affinity target

49
Q

what is aquired resistance

A

Acquired resistance: Strain is typically susceptible to a given antimicrobial drug and becomes resistant.
-ex: inactivation of druh

50
Q

how does antibiotic resistance spread withinm a population

A

vertical and horizontal gene transfet

51
Q

Vertical genetic transfer of resistance
mutations

A

This selects an advantageous mutation (resistance mutation) that occurred as a random genetic event into a major genetic allele through clonal expansion

52
Q

Horizontal genetic transfer of
resistance genes or mutations

A
  • Major mechanism spread within and
    across hosts, different environments and bacterial species
  • Plasmid-borne transfers can allow multiple resistance genes to be spread at once
53
Q

true or false: resistance genes often originate from antibiotic producing species or other resistant bacteria

A

true

54
Q

true or false: newly acquired resistance genes can be selected for under antibiotic treatment

A

TRUE

55
Q

NAME the eskape pathogens

A

Enterococci faecium
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter sp.

56
Q

who top priorities

A
  • Tuberculosis
  • Gram negative bacteria
  • Resistance to antibiotics of “last resort”:
  • ESBL (extended spectrum betalactamase) and MBL (metallo
    beta-lactamase)
  • Colistin resistance
57
Q

AMR outside the clinic

A
  • Antibiotic use for growth promotion, disease prevention and treatment
  • Use of medically used antibiotics
  • Off label use of antibiotics highly similar to human antibiotics
58
Q

antibiotic resistance; what can you do

A

-only take antibiotics when have to
-tajke full prescription
-never use left over antibiotivs
-never share antibiotiocs
-wash your hands and don’t tal;k to sick people

59
Q

true or false: no new class of antibiotics discovered since 1987 has yet led
to new drugs

A

true

60
Q

No new antibiotics introduced between … and ….

A

2003-2011tr

61
Q

true ot false: the antibiotic pipeline is less bad npw

A

true

62
Q

total approved antibiotics since 2014:

A

14

63
Q

total discontinued antibiotics since 2014

A

19

64
Q

Penicillin, the 1st antibiotic (1928, Sir Fleming) produced by the …

A

mold Penicillium

65
Q

Streptomycin, the first screen for antibiotics (1943, Selman Waksman) what was done

A
  • Screened >10,000 soil organisms
  • Streptomycin, first aminoglycoside produced by Streptomyces griseus
66
Q

Antibiotic-producing micro-organisms: soilorganisms such as ….

A

Actinomyces and Streptomyces, fungi/mold

67
Q

Antibiotic have been made by bacteria for over …` millions years

A

40

68
Q

Natural products; strategies

A
  • Natural compound libraries
  • Libraries of micro-organisms (natural isolates)
  • Screen natural samples for antibacterial activity: soil and marine bacteria, fungi, marine invertebrates (e.g. sponges, corals)
  • Probably need to screen many strains (107 ?) to find one compound
69
Q

Screening of synthetic molecule libraries

A
  • hundreds of thousands/millions of molecules
  • In vitro screening yielded little success
  • Whole cell assays more difficult
70
Q

Synthetic biology

A
  • genome mining for biosynthetic clusters
  • “natural” or recombinant expression of antibiotic-producing operons
71
Q

Chemical optimization:

A
  • Improve penetration inside cells: increased membrane penetration or
    uptake, greater stability, better activity against target
  • Improve pharmacokinetic/pharmacodynamic
  • Overcome resistance mechanisms: reduced efflux, drug degradation or
    modification
72
Q

Combination therapy (with adjuvants)

A
  • Add another antibiotic: e.g. trimethoprim-sulfadiazine, multi-drug TB regimens
  • Molecule to overcome resistance: e.g. ampicillin + clavulanic acid
  • Molecule that increases penetration: e.g. cephalosporin siderophore
73
Q

Repurposing of drugs already approved

A

Non-antibiotics which show antibacterial activity: e.g. antipsychotics

74
Q

target protein+chemical library..

A

=target specific assay (high throughput screening)=phenotypic evaluation

75
Q

cell/ organism model+ chemical library…

A

=phenotypic assay(high content screeniong)=target devolution

76
Q

teixobactin

A

Teixobactin kills bacteria by a two-pronged attack on the cell envelope
without resistance

77
Q

Cefiderocol

A

Cefiderocol for the Treatment of Infections Due to Metallo-B-lactamase–Producing Pathogens in the CREDIBLE-CR and APEKS-NP Phase 3 Randomized Studies

78
Q
A

mimm 465 (6 decks)

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