Antibiotic Resistance Flashcards
Where did most antibiotic resistance most likely emerge from
overuse of antibiotics in agriculture
misuse of antibiotics in humans: 50% inappropriate use, wrong dosage or duration such as in a viral infection
there are 25 million pounds of non therapeutic livestock use and there are about 3 million pounds of human medical use
What does MDR stand for
multidrug resistant
resistant to three or more antibiotic categories
How many antibiotics are MDR (multi drug resistant) bacteria resistant to
resistant to three or more antibiotic categories
What does XDR stand for
extensively drug resistant
susceptible to two or fewer antibiotic categories
only two or one antibiotic category would work
What does PDR stand for
pan drug resistant
not susceptible to any of the approved drugs in all categories
How many antibiotics are XDR (extensively drug resistant) bacteria resistant to
only susceptible to two or fewer antibiotic categories
How many antibiotics are PDR (pan drug resistant) bacteria resistant to
not susceptible to any of the approved drugs in all categories
There are the 6 well known multi drug resistant pathogens
Enterococcus spp. VRE
Staphylococcus aureus MRSA
Klebsiella spp. CRE
Acinetobacter baumannii ESBL
Pseudomonas aeruginosa ESBL
Enterobacter spp. CRE
What are the main mechanisms of antibiotic resistance
- restriction of the antibiotic to the antibiotic target
- enzymatic inactivation of the antibiotic
- modifying the antibiotic target
- protecting the antibiotic target
- failure to activate the antibiotic
- restriction of access to target: outermsmbrane barrier, selective porins, efflux pumps
- enzymatic inactivation: beta-lactamase, aminoglycoside modifying enzymes, CAT
- target modification or protection: PBPs with reduced affinity for beta lactase, point mutations that alter affinity of DNA gyrase to fluoroquinolone, RNA polymerase mutations alter affinity to rifampin, 23S rRNA mthylases, D-ala-D-lac substations
- failure to activate the antibiotic: metronidazole is a prodrug requiring reduction by bacterial flavodoxin to active form, reduced expression to flavodoxin
What are examples of restriction of the antibiotic to the antibiotic target
outer membrane barrier
selective porins
efflux pumps
What are examples of enzymatic inactivation of the antibiotic
beta-lactamase
aminoglycoside modifying enzymes
CAT
How do outer membrane porins work against antibiotics
outer membrane: formidable barrier
outer membrane porins are selective gatekeepers
How do outer membrane porins work against antibiotics
outer membrane: formidable barrier
outer membrane porins are selective gatekeepers
small molecules can diffuse to periplasm through porins
antibiotics such as vancomycin and daptomycin are too large to get through porins and the outer membrane
What types of antibiotics do porins prevent/ how does this process work/ what type of antibiotic resistance is this
vancomycin and daptomycin are too large to diffuse through the periplasm through porins
usually small molecules diffuse through porins into the periplasm
restriction of access of the antibiotic to its target
How do antibiotic efflux pumps work against antibiotics
efflux pumps have been discovered for nearly every class of antibiotic
gram - efflux pumps span both membranes and is analogous to type I secretion system
gram + efflux pumps are simple anti-porters or ABC transporters
What type of efflux pump do gram - bacteria have
span both membranes and is analogous to type I secretion system
What type of efflux pump do gram + bacteria have
are simple anti-porters or ABC transporters
An efflux pump is a type of ____ antibiotic resistance mechanism
restriction to access of the antibiotic to its target
How do serine beta-lactamases work against antibiotics
cleave the beta-lactam ring of antibiotics
similar mechanism to the beta lactams action on the transpeptidase enzyme
Are serine beta-lactamases more common in gram - or gram +
more common in gram negative bacteria
How do zinc beta-lactamases work against antibiotics
cleave the antibiotic at a different site
clavulanic acid and other inhibitors cannot interact with the zinc form
can cleave a wider range of beta lactams than serine beta-lactamases
used against Carbapenems: Doripenem, Meropenem, Imipenem
What does clavulanic acid do
inactivates beta-lactamase in when added with SERINE beta-lactamases used with penicillin, cephalosporins: Ceftazidime, Cefotaxime, Ceftriaxone???
clavulanic acid and other inhibitors cannot interact with the ZINC form
When is clavulanic acid usually administered with
beta lactams can be administered in combination with a beta lactase inhibitor bc the clavulanic acid inactivates beta lactamases in SERINE beta lactamases
clavulanic acid and other inhibitors cannot interact with the ZINC form
What type of antibiotic resistance mechanism do serine beta lactamases and zinc beta lactamases
enzymatic inactivation
What type of antibiotic resistance mechanism is aminoglycosides
enzymatic inactivation
inactivated by the addition of modifying groups
modifications disrupt interaction of the antibiotic with its cellular target (30S ribosome via 16S rRNA)
How do aminoglycosides work against antibiotics, what antibiotics are most likely to be inactivated against this
inactivated by the addition of modifying groups
modifications disrupt interaction of the antibiotic with its cellular target (30S ribosome via 16S rRNA)
Kanamycin and Gentamycin
What type of antibiotic resistance mechanism is the penicillin-binding protein resistance in bacteria
target modification
How does the penicillin-binding protein resist against antibiotics what type of antibiotics are most susceptible, what type of bacteria uses this
modification prevents binding of beta lactase ring
involves modification of existing amino acids
clavulanic acid cannot block this type of resistance
common in gram + bacteria MRSA/VRE
mutations in penA gene confers resistance of PBP to Cephalosporins in N-gonorrhoeae
mutations in mecA gene codes for novel PBP with reduced affinity for beta lactams
What type of antibiotic resistance mechanism is vancomycin resistance in bacteria
target modification
How does vancomycin resist against antibiotics what type of antibiotics are most susceptible, what type of bacteria uses this
conjugative transposons/plasmids
the antibiotic normally prevents the peptide inter bridge from forming, by binding strongly to D-ala-D-ala residues in the stem peptide
this prevents the transpeptidase from linking the cross-bridge
modifys D-ala-D-ala to D-ala-D-lac
vancomycin binds D-ala-D-lac 1000 times less effective than D-ala-D-ala which explains resistance
What type of antibiotic resistance mechanism is macrolide resistance in bacteria
target modification
How does macrolide resistance work
RNA methylates can add methyl groups to reside A2058 in the 23S RNA target site of the ribosome
the antibiotic can no longer bind to the large subunit and block the polypeptide exit
What type of antibiotic resistance mechanism is used by TetO, TetM, and TetQ mediating tetracycline resistance
ribosomes protection by TetO, TetM, and TetQ that mediate tetracycline resistance
target protection
How does TetO, TetM, and TetQ mediating tetracycline resistance work
ribosomes protection by TetO, TetM, and TetQ that mediate tetracycline resistance
addition to efflux based
How does TetO, TetM, and TetQ mediating tetracycline resistance work
ribosomes protection by TetO, TetM, and TetQ that mediate tetracycline resistance
in addition to efflux based systems that clear tetracycline from the cell
a new modified version of tetracycline called glycylglycines overcome these resistance mechanisms
What type of tetracycline can overcome tetracycline resistance
glycylglycines
What type of antibiotic resistance mechanism is used by metronidazole resistance
failure to activate
How does metronidazole resistance work
failure to activate the antibiotic
activated by flavodoxin
damages DNA by causing nicks
no active form: no nick: no drug sensitivity
flavodoxin reduces the nitro group on the inactive from of metronidazole and this changes the active form and H. pylori decreases the expression of flavodoxin which decreases the active from expression
How are H.pylori resistant to antibiotics
metronidazole resistance
metronidazole is activated by flavodoxin which damages DNA and causes nicks
flavodoxin reduces the nitro group on the inactive from of metronidazole and this changes the active form and H. pylori decreases the expression of flavodoxin which decreases the active from expression
no active form: no nick: no drug sensitivity
failure to activate
How does isoniazid resistance work
Isoniazid is activated by KatG (catalase), Isoniazid blocks mycotic acid synthesis
no active form, no inhibition of cell wall, no drug sensitivity
resistance stems from altered expression or function of KatG
What type of antibiotic resistance mechanism is used by isoniazid resistance
failure to activate the antibiotic
What is the genetic linkage between multi drug resistance bacteria
some plasmids contain independent genes involved in antibiotic resistance
What are persisters and how do they lead to persistent
- bulk population that an antibiotic is added to
- some persisters are a small sub population of cells that temporarily stop dividing and then the antibiotic is removed
- there is a repopulation of bacteria and then the an antibiotic is added again
- the majority of bacteria die but some persisters remain
