Antibiotic Resistance Flashcards
What is the problem with drug resistant bacteria?
we cant treat them
drug resistant pathogens are not more pathogenic- just less antibiotics work on them
What is MRSA?
Methicillin resistant Staphylococcus aureus
Gram positive pyogenic diplococci
What does MRSA cause?
surgical sepsis and endocarditis
How did staph aureus become resistant to antibiotics?
before antibiotics was made= staph would cause infection= lead to sepsis, endocarditis= lead to death
when antibiotics made= worked against staph
2 years later (1949)= became resistant (8%)
7 years later = became resistant (70%)
it became resistant bc it acquired a gene for beta lactamase from other bacteria = could break penicillin down
In 1956, what new antibiotics were made against staph?
chloramphenicol, tetracycline, and streptomycin
staph became resistant to these too (through mutations)
What is the most recent antibiotic against staph?
methicillin adaptation of penicillin doesnt react to beta lactamase in1978, all resistant THIS IS MRSA
How can you treat staph now?
vancomycin
How can we get resistance against vancomycin?
enterococci (gram positive)= live in gut= naturally resistant to vancomycin= cause no problem
acinetobacters (gram negative)= live in gut= multiply resistant= they have genes coding for penicillin binding proteins and different enzymes that break down carbapenems (carbapenemases)
if someone has MRSA wound infection, they sometimes have MRSA in gut
the bac swap DNA (so MRSA can get genes from enterococci and acinetobacters)= cause resistance
What are enterococchi?
- (gram positive)
- live in gut
- naturally resistant to vancomycin
- normally cause no problem
What are acinetobacters?
- gram negative
- live in gut
- multiply resistant
- they have genes coding for penicillin binding proteins and different enzymes that break down carbapenems (carbapenemases)
What is gentamycin?
antibiotic
protein synthesis inhibitor
What are the different mechanisms for antibiotic resistance?
bacteria degrade/modify drug by getting enzymes
bacteria modifies drug targets
bacteria blocks entry of antibiotics into bacteria
bacteria does BYPASS
in lec slide:
What enzymes does a bacteria have to degrade drugs?
- beta lactamase = break down beta lactam ring in some antibiotics
- chloramphenicol acetyl transferase = transfers acetyl group to chloramphenicol which modifies the chloramphenicol making it inactive
How does a bacteria modify drug targets?
- antibiotics can work at many places: protein synthesis, cell wall synthesis, inhibit DNA gyrase, inhibit RNA polymerase, inhibit folic acid synthesis etc
- if the bacteria acquires a different target that is no longer bound by the antibiotic, the bacteria becomes resistant
e. g. penicillin binding proteins are an example of a target
How are penicillin binding proteins a target?
- PBP= enzymes that cross link peptidoglycan cell wall
- bacteria have many genes coding for the enzymes
- genes are always swapping
- PBP can be inhibited by simple penicillin
How do antibiotics get across into bacteria?
- antibiotics- naturally hydrophobic surface- cant get across
- get in through influx pumps
(bacteria also produce efflux pump to get antibiotic out (at same rate as coming in))
How does bacteria block the entry of antibiotics?
upregulate efflux pump
pumps out antibiotics faster than they come in
now not enough amount of antibiotic in the bacteria
so bacteria become resistant
What happens if you have a single mutation of the influx pump?
antibiotics cant enter
What does sulphonamide do?
- antibiotic
- blocks dihydropteroate synthase (part of pathway to produce folic acid)
What does bypass do?
- used for sulphonamide
- some bacteria upregulate the process of generating the substrate for dihydropteroate synthase (para-amino benzoic acid)
- the metabolic pathway progresses much faster, and not enough antibiotic gets to the bacteria to block this process
What are the 3 mechanisms to resistance?
natural resistance
genetic resistance
non-genetic resistance(called tolerance)
Natural resistance: name a bacteria which has such a structure that makes it hard for antibiotics to get through?
pseudomonas (gram negative)
has mucous surface- hard for antibiotic to get through
What does gram positive bacteria have allowing it to have natural resistance?
lots of peptidoglycan
highly porous
so no diffusion barrier for antibiotics to get to enzymes
What does gram negative bacteria have allowing it to have natural resistance?
has outer membrane- barrier to antibiotics
What are the 2 main genetic mechanisms through which bacteria get resistance?
chromosome mediated
plasmid mediated
How do chromosome mediated mechanisms work?
spontaneous mutation in bacteria
most bacterial genomes are about 4 million base pairs long, and they rapidly divide every 20 mins-its very easy for mutations to arise if they are replicating to numbers of10^6 to 10^7
if this mutation happens where antibiotics bind, then it becomes resistant
Where can a mutation be in order to avoid antibiotics coming into the bacteria?
in target molecule
in drug uptake system (e.g. porins in gram negative bacteria)
How does plasmid mediated mechanism work?
acquired genes in plasmid or transposomes (small circular DNA in bacteria)
genes can be transferred between different bacterias i.e. genes that have mutli antibiotic resistance
How can bacteria transfer genes?
transformation
transduction
conjugation
What is transformation?
any bacteria can take up DNA from the environment, dying bacteria release their DNA into the environment which is picked up by growing bacteria
What is transduction?
- bacteriophage= virus- infects bacteria
- bacteriophage integrate into genome
- come out of genome to infect next bacteria
- as they do this, they take some genetic material
transfer it to another bacteria
What is conjugation?
- bacteria come together
- exchange genetic information
What do beta lactams do?
antibiotics (penicillin and cephalosporin)
inhibit cell wall synthesis
block trans and carboxy peptidases= involved in cross linking of peptidoglycan
What do gram positive and gram negative organisms produce?
beta lactamase= breaks down penicillin
What is augmentin/co-amoxiclav?
- combines amoxicillin (broad spectrum penicillin) with clavulanic acid
- binds to and inactivates beta lactamases
- clavulanic acid has no antibacterial activity, but is a competitive inhibitor of the beta lactamase enzyme which would normally break down amoxicillin
What do gram positive bacterias have?
beta lactamase
alter PBP
What do gram negative bacterias have?
beta lactamase
alter porins
What are the 3 mechanisms in gram negative bacteria to prevent antibiotics?
make new porin
change PBP
beta lactamase
How does vancomycin work?
- Vancomycin binds to D-Ala –D-Ala residues on the NAM subunit of cell wall precursors
- bc of this, enzymes like transpeptidases and enzymes that polymerize the sugar part of the peptidoglycan get blocked
- they can no longer attach to their substrate (which is D-Ala –D-Ala)
How do you get vancomycin resistance?
- bacteria have mutated and acquired a whole set of genes called the van operon through a transposition event
- instead of making peptidoglycan with terminal D-Ala –D-Ala, they now make D-Ala –D-Lac and now the drug does not bind very well to it
- there are not as many hydrogen bonds between the drug and the terminal peptides as before−and so the drug does not work very well now
In infections, what happens to bacterial growth?
bacteria grow rapidly and then reach stationary phase (population which has done lots of growing)
Give an example of bacteria in the stationary phase:
- heart valves (someone with endocarditis)
= vegetative growth of bacteria on heart valves- (doesnt grow anymore
= has bio film mucus layer outside= impermeable to antibiotics
= trying to treat someone with endocarditis is hard bc antibiotics dont go accross biogilm and antibiotics cant work against bac targets bc they are not growing so not making protein, replicating, DNA, synthesizing peptidoglycan.
How do you prevent antibiotic resistance?
- Control the use of antibiotics- complete course, prescribe appropriately
- Find new or modified drugs
- Combination therapy-use drugs together as this will lead to different targets and overcome mutation rates
- Infection control
What used to be used to treat Neisseria gonorrhoea?
- used to swab genital area for gram negative diplococci
- give penicillin= IM
- people started getting resistant to it
- penicillin switched to ciprofloxacin
- people became resistant
- then changed to oral single dose of oral cephalosporin called cefixime (B lactam ring antibiotic)
- people became resistant
- NOW: intramuscular dose of ceftriaxone + 1g oral dose of azithromycin
What is a carbapenem?
beta lactam antibiotic
treat gram negative organisms
How are bacteria getting resistant to carbapenem?
making carbapenemases
new strains of bacteria are getting nmd1 (resistance to broad spectrum of beta lactamases)
Which antibiotic works against UTI?
colistin
the Antibiotic attacks membrane, is toxic
