5. New developments in (fluoro)quinolone Resistance Flashcards
1. Describe the mechanism of action of quinolone antibiotics. 2. Describe mechanisms of quinolone resistance. 3. Discuss how different mechanisms can work together to confer resistance.
What are quinolones?
- They are synthetic antibiotics.
- They were relatively recently discovered in the 60s
- They are topoisomerase inhibitors.
How were quinolones discovered?
- Scientists were trying to quinine into a better anti-malaria treatment.
- Quinolones like Nalidixic acid were a product of this program.
- They failed to find antimalarials, but these had strong antibiotic activity when tested
What is Nalidixic Acid?
- The 1st quinolone.
- It is used to treat gram negative bacteria.
- They are used in humans and was moderately effective in humans.
- It has some issues with resistance and adverse pharmacological properties.
Why is Nalidixic acid unusual?
It mainly treats gram-negative bacteria. This is strange as gram-positives are easier to treat due to its membrane.
Why were quinolones developed into fluoroquinolones?
- There was a need for better treatment for GI infections like salmonella and shigella.
- There was a need for more and better gram-negative treatment.
How are 2nd generation (Fluoro)quinolones different from 1st generation?
- They have the addition of fluorine on carbon six on one of the rings.
- This expands their spectrum of activity to make it very potent against gram-negative bacteria.
What is the main 2nd generation (fluoro)quinolone and how is it different from 1st gen quinolones?
- Ciprofloxacin
- Contains the fluorine at carbon 6 as well as the addition of a 6 membered ring that contains a nitrogen and a piperazinyl groups.
What is a piperazinyl group?
A carbon ring with a nitrogen and a free NH group.
What increases the spectrum of activity of quinolones?
The addition of extra chemical groups
What additions were made to make 3rd generation quinolones?
Different chemical groups are added to the free N on the piperazinyl group. eg a methyl group
What can 3rd gen quinolones treat?
- The gram-negative GI etc infection of the previous generation
- Expanded to treat gram-positive infections like respiratory tract infections.
What is an example of 3rd gen quinolones?
Levofloxacin
What additional chemical groups were added to make 4th generation quinolones?
In the piperazinyl group, a carbon is changed to a nitrogen
What can 4th gen quinolone treat?
Everything the previous generations can with the addition of anaerobic infections.
They are very broad spectrum and very potent.
What is the base structure of quinolones?
a bicyclic ring
Additions to the quinolone base structure: carbon 1
These increases the overall potency.
Additions to the quinolone base structure: carbon 5
These increase the gram-positive activity
Additions to the quinolone base structure: carbon 6
Fluorine addition increases the gram-negative activity
Additions to the quinolone base structure: carbon 7
Additions of groups like piperazinyl increase the gram-negative and gram-positive activity
Additions to the quinolone base structure: Position 8
These increase activity to cover anaerobes and expand the gram-positive activity.
What is the clinical importance of (Fluoro)Quinolones?
- They are broad spectrum.
- Treat UTIs, Bacterial diarrhoea and pneumonias.
- They can treat some anaerobic infections
- They are synthetic agents
Why are quinolones being synthetic agents attractive?
- Naturally produced antibiotics have intrinsic resistance mechanisms in the organisms that make them and organisms that live in the same niche.
- This prevents them from being killed by their metabolites but they can mobilise to make resistant infections.
- Synthetic compounds would be expected not to have intrinsic resistance mechanisms which make them desirable.
- However this is not the case
What is the problem with quinolones?
- As they are used more, it has become apparent they can have very serious side effects.
- Joint damage, muscle damage, neurological complications, and adverse mental health effects.
- This has caused very tight regulation on their use to limit them to serious and complex infections.
- Due to this, it is expected quinolones will decline in use even more.
How do quinolones work?
They are bacteria type 2 DNA topoisomerase inhibitors.
How do bacteria package their DNA and what problems does this create?
- They have circular chromosomes and plasmids and they need to package it efficiently using supercoils.
- Fundamental processes like DNA replication and transcription puts the DNA under torsional stress and effects it topology.
- If this is not countered, the stress can break the DNA.
- During replication, the chromosomes are linked and need to be separated.
- This is done by topoisomerases
What do type 2 topoisomerases do?
- They control the shape and topology of the DNA.
- DNA gyrase controls super coiling in the negative direction.
- Topo 4 controls supercoiling in the positive direction.
- Topo 4 can also separate the chromosomes from replication.
- They are essential for cell function, so they make a good drug target.
What do quinolones target?
The type 2 topoisomerases DNA gyrase and Topo 4.