Introduction antibacterial discovery Flashcards
- MDR / XDR-TB
- MRSA
- Resistence Mycobacterium tuberculosis
- Multi drug resistant S. aureus
Also viruses and parasites become resistant
But HIV / malaria easier to develop new antibiotics
Bacteria are more complex organisms and use various ways to develop drug resistance
Infectious with major issues in DALY (disability adjusted life year)
- Parasites: Malaria
- Virus : HIV/AIDS
- Bacterial: Tuberculosis, Diarrhea
History:
Tetracyclin resistance and solution
- Resistance against tetracyclin by expression of efflux pump
Solution: synthetic tailoring > tetracyclin no longer recognised by efflux pump. But don’t change the part that bind the ribosome
- Keep scaffold, but change side groups
Scaffold
Common core structure that executed the biological activity
Example beta lactams:
Normal function
- Beta lactams normally inhibit transpeptidase PBP.
Each beta lactam (made by synthetic tailoring) has different activities
> Because each pathogen has different combinations of PBP’s with different sensitivities.
Beta lactamases and resistance mechanism
2 solutions against resistance
Resistance mechanism:
- Modify PBP
- Decrease permeability outer membrane
- Efflux beta lactams
- Bypassing normal PBPs (most common)
- Beta lactamases: Different classes hydrolyze beta lactams in different efficacy of cleaving
Solution:
- Add beta lactamase inhibitors in therapy
- Modify beta lactam , so enzyme can’t bind
But not to far because they should be able to bind PBP.
Novel scaffold discovery of new mechanisms of inhibition:
Boosted by genomics
Boosted by genomics since nineties. Availability of genome sequences.
- Synthetic libraries for sequencing : Major strategy, screen large compound libraries for inhibitors.
- Screen pathogen:
- High througthput screening: Start with library with at least 100.000 compounds and
> Screen target molecule (enzyme function)
> Screen pathogen growth function
> Screen in infection models
New scaffolds from natural products,
From jaren 2000 realization
4 facts
- In evolution nature has came up with potent antbiotics.
- Natural compounds have evolved over the years to effectively kill other microorganisms, with acquired all required properties
- 2/3 clinically used antibiotics are derivates of natural compounds
- Soil microorganisms were screened
Synthetic libraries have some serious limitations
- Limited by synthetic pathways: We can’t make everything
- Limited knowledge of requirements for an antibacterial compound
Most antibiotics from streptomyces
5 Facts
- Bacterium in soil
- Belongs to actinomycetes
- Largest bacterial genera
- Grow easy in lab
- Similaraties with fungi in soil, Results from adaptations to similar ecological niches
Life cycle of streptomyces
- Grow as brancing hypae that form a vegetative mycelium
- Verspreiden through pores that form on specialized reproductive structures called hypae
- Similaraties with fungi»_space; Need to compete with fungi for nutrients > So kill other organisms in soil
Biological metabolietes
Can be used for antibiotics. Produced by actinobacteriae.
Concept low hanging fruits
3 facts
- Small fraction of existing microbial diversity has been systemically sampled
»_space; Limited micro organisms can grow in a lab - Only the most activa antibiotics have been identified
»_space; Detection is limited to sensitivity of the assay - Finding antibiotics is a number game
» Screening of many strains is required to find a good one.
How to find new soil bacteria?
- Some could not grow in lab»_space; Made special chip and let bacteria grow in natural surrounding.
- Some soil micro organisms live in symbiosis: So grow them also together in lab
