Antibiotic Resistance - Photolabile Flashcards
What are the causes of antibiotics resistance?
natural selection and evolution
- mutation
- transfer of genes
overuse and misuse
- overprescribing
- incomplete treatment
How does drug resistance by mutation occur?
bacteria acquire resistance through spontaneous mutations in their genetic material
target site modification
efflux pumps
enzyme modification
How does resistance occur by genetic transfer?
involves the acquisition of resistance genes by bacteria through mechanisms of horizontal gene transfer
- transduction
- conjugation
What is horizontal gene transfer?
the non-sexual movement of genetic information between genomes
- sharing of genetic material between organisms that are not in a parent–offspring relationship.
What is transduction?
transfer of genes from recipient to donor through bacteriophages
- a bacteriophage infects a donor bacterium, incorporates the bacterial DNA into its own genetic material then releases new phage particles
- when these phages infect a recipient bacterium, they may introduce the antibiotic resistance genes
- this leads to the acquisition of antibiotic resistance by the recipient bacterium
What is a bacteriophage?
viruses that infect and replicate only in bacterial cells
consist of a nucleic acid genome encased in a shell of phage-encoded capsid proteins, which protect the genetic material and mediate its delivery into the next host cell.
What is conjugation?
involves direct transfer of genetic material between bacterial cells
often carried on plasmids from a donor to a recipient bacterium
genetic material is transferred though a bridge structure called a pilus
- pilus pulls the bacterium close
What are the factors affecting drug resistance?
differential acquisition of resistance
- bacterial species variation
- mechanism specific variation
- selective pressure and use of antibiotics
- specific organism characteristics
evolution of resistance and global disparities
- healthcare access and practices
- antibiotic use
- economic disparities
- healthcare systems and surveillance
- global travel and trade
- socioeconomic factors
animal feeding
- antibiotic use in agriculture = therapeutic
- antibiotic use in agriculture = sub-therapeutic
- environmental contamination
- human health impact
What are practical approaches to overcoming antibiotic resistance?
Optimising the administration of currently available antibiotics
Antibiotic modification – resistance to resistance mechanisms
Photolabile antibiotic – self-destruct mechanism
Drug combinations
How can kanamycin be modified to gain resistance to resistance mechanisms?
kanamycin is an aminoglycoside
resistance mechanism
- resistant bacteria phosphorylate one of the hydroxyl groups (alcohol) present which inactivates kanamycin due to the structural change
resistance to resistance mechanism
- an active analogue replaces the susceptible alcohol group with a ketone (prodrug)
- the ketone is in equilibrium with the hydrated gem-diol (active form)
- when phosphorylation occurs on the diol, the phosphate group acts as a good leaving group and the ketone is regenerated
How are antibiotics introduced to the environment?
resistant faecal strains of bacteria from antibiotic-fed farm animals are present in their manure
- spread of resistant bacteria occurs as the manure is applied to fields
= it is used as fertiliser in agricultural lands
this practice accelerates the dissemination of resistant bacteria into the ecosystem
How can the issue of antibiotic introduction into the environment be solved?
could be reduced by incorporating a self-destruct mechanism which is triggered once the antibiotic is excreted
the light induced unmasking generates a reactive functionality which destroys the beta lactam moiety of beta lactase thereby inactivating it
How does modified cephalosporin work as a photo labile antibiotic?
a modified cephalosporin has a protected hydrazine group
- the protecting group is the ortho nitrobenzylcarbamate group which is susceptible to light
once the antibiotic is excreted and exposed to light, the nitrobenzylcarbamate protecting group is lost
this allows the nucleophilic hydrazine moiety to react with the beta lactam ring and deactivate the molecule
- open up the beta lactam ring which is the moiety which accounts for antibiotic activity
How do different drug combinations work?
synergistic effects
- the combined effect is greater than the sum of their individual effects and increases the overall efficacy
= trimethoprim/sulfamethoxazole
expanding spectrum of activity
- involves combining antibiotics with different mechanisms of action
= amoxicillin/clavulanic acid
preventing resistance
- using multiple antibiotics simultaneously can make it harder for bacteria to develop resistance
= rifampicin/isoniazid
reducing doses
- combinations can allow for the use of lower doses of each antibiotic
= H.pylori treatment involves 3 antibiotics + 1 PPI
