antibiotics: mode of action and mechanisms of resistance. · by senior scientist henrik hasman...
TRANSCRIPT
![Page 1: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/1.jpg)
BySenior scientist Henrik Hasman
National Food Institute-DTU
Antibiotics: mode of action and mechanisms of resistance.
![Page 2: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/2.jpg)
2
What are antibiotics?
Originally:Naturally occurring microbial products
Today:Any agent used to treat infections
![Page 3: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/3.jpg)
3
Mechanisms of antibiotics
• Bacteriostatic
• Bactericidal
![Page 4: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/4.jpg)
4
Bacteriostatic antibiotics• Tetracyclines
• Spectinomycin• Sulphonamides• Macrolides• Chloramphenicol• Trimethoprim
![Page 5: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/5.jpg)
5
Bactericidal antibiotics• Penicillins• Cephalosporins• Fluoroquinolones (Ciprofloxacin)• Glycopeptides (Vancomycin)• Monobactams• Carbapenems
![Page 6: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/6.jpg)
6
What is antimicrobial resistance I?
The ability of a microorganism to survive at a given concentration of an antimicrobialagent at which the normal population of the
microorganism would be killed
This is called the “Epidemiological breakpoint”.
![Page 7: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/7.jpg)
7
=
0
10
20
30
40
50
60
0,25 0,5 1 2 4 8 16 32 64 128 256
MIC
Num
ber o
f iso
late
s Sensitive population
Break point
Resistant population
Population distribution
![Page 8: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/8.jpg)
8
What is antimicrobial resistance II?
The ability of a microorganism to survive treatment with a clinical
concentration of an antimicrobial agent in the body.
This is called the “Clinical breakpoint”.
![Page 9: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/9.jpg)
9
Antibiotics: Modes of action
• Inhibitors of DNA synthesis
• Inhibitors of bacterial protein synthesis
• Inhibitors of bacterial cell wall synthesis
![Page 10: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/10.jpg)
10
From DNA to protein
RNA polymerase
Ribosome
RNA polymerase
A G
T C
Nucleotides
![Page 11: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/11.jpg)
11
Cell wall syntesis:CycloserineVancomycin (glycopeptides)BacitracinPenicillinsCephalosporinsMonobactamCarbapenems
DNA gyrase:Naldixcin acidNarfloxacinNovobiocinQuinolones
RNA polymerase:Rifampicin
Protein syntesis(60S inhibitorer):Makrolider(erythromycin)ChlorampinicolClindamycinLincomycinStreptograminsOligosaccharides
Protein syntesis(30S inhibitorer):TetracyclinSpectinomycinStreptomycinGentamycinTobramycinKanamycinAmikacin
DHF
THF
PABA
Folic acid metabolism:TrimethoprimSulfoamids
(PABA= p-aminobenzocis acid, DHF=dihydrofolate, THF=tetrahydrofolate (essential for growth of bacteria))
Genetic characterisation to study Spread of antimicrobial resistance
Targets in the bacterium
![Page 12: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/12.jpg)
12
Bacterial growth
![Page 13: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/13.jpg)
13
Penicillin
Inhibition of cell wall synthesis
![Page 14: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/14.jpg)
14
Antibiotics: Modes of resistance
![Page 15: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/15.jpg)
15
Resistance mechanisms I
• Point mutations in target genes/influx pumps
![Page 16: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/16.jpg)
16
110 120 130 140 150 NalS 101 TGACGTAATC GGTAAATACC ATCCCCACGG CGATTCCGCA GTGTATGACA NalR MUT83A 101 TGACGTAATC GGTAAATACC ATCCCCACGG CGATTACGCA GTGTATGACA NalR MUT83T 101 TGACGTAATC GGTAAATACC ATCCCCACGG CGATTTCGCA GTGTATGACA
Codon 83: TCC TTCTAC
Genetic variations/Point mutations
PheTyr
Ser
DNA gyrase –quinolone resistance
![Page 17: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/17.jpg)
17
Resistance mechanisms II
• Acquired genes
![Page 18: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/18.jpg)
18
E. coli/ salmonella
Acquisition of resistance
![Page 19: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/19.jpg)
19
vanA
Origin
erm(B)
tcr
175 kb
tcr=Transferable copper resistance
Co-selection of resistance
Usage of copper or erythromycin selects for presence of vancomycin resistance
![Page 20: Antibiotics: mode of action and mechanisms of resistance. · By Senior scientist Henrik Hasman National Food Institute-DTU Antibiotics: mode of action and mechanisms of resistance](https://reader030.vdocument.in/reader030/viewer/2022021610/5b8244937f8b9a466b8e2033/html5/thumbnails/20.jpg)
20
Emerging problems
– Fluoroquinolones-resistant Salmonella– 3rd gen. Cephalosporin-resistant Salmonella (ESBL)– Fluoroquinolone- and macrolide-resistant Campylobacter– Vancomycin resistant enterococci (VRE)– (Multiresistant E. coli)– MRSA in animals (report of high prevalence of MRSA in pigs
in the Netherlands - now also found in Danish animals).
Antimicrobials and resistance problems