M10: Antimicrobial Resistance Mechanisms Flashcards
Antimicrobial Resistance:
Antibiotic resistance is (a major / not a) problem for contemporary medicine.
The annual cost of bacterial drug resistance is estimated to run between $100 million and $30 billion.
It is important to note that antimicrobial resistance in bacteria is a (local / global) problem.
The problem is even more critical as we face the emergence of some _ organisms for which there are no effective antimicrobial regimens.
a major
global
multi-resistant
Where Does Antibacterial Resistance Come From?
There are several potential sources of antimicrobial resistance in bacteria.
One common source is via the introduction of _ from _.
An important example of this is the introduction of the USA 300 clone of _ which is the prominent strain associated with the epidemic of community-associated _ in the USA.
resistant strains
outside the “community”
Staphylococcus aureus
MRSA
Where Does Antibacterial Resistance Come From?
There are several potential sources of antimicrobial resistance in bacteria.
A second important source is the acquisition of _ from _.
This may be accomplished through the acquisition of _ elements such as _ or _.
antimicrobial resistance
another strain
mobile DNA
plasmids or transposons
Where Does Antibacterial Resistance Come From?
There are several potential sources of antimicrobial resistance in bacteria.
Emergence of resistance can also occur as a consequence of a _ in the _.
An example of this would be development of a mutation in the _ which alters the affinity of macrolide antibiotics to _ and _, rendering them essential inactive.
spontaneous mutation
bacterial genome
23s ribosome
bind to their target
block protein synthesis
Where Does Antibacterial Resistance Come From?
There are several potential sources of antimicrobial resistance in bacteria.
The last important source of resistance is the selection of _ via _.
This differs slightly from mutation alone as it combines the natural occurrence of _ with the selective pressure of _.
resistant strains
antibiotic pressure
genetic mutation
broad exposure to antibiotics
Mechanisms of Antibacterial Resistance:
There are 4 major mechanisms of antibacterial resistance.
Together, these 4 mechanisms essentially account for (all / most) of the methods that bacteria manifest antimicrobial resistance.
These mechanisms include:
1) the presence of _ that _ or _ antibiotics
2) synthesis of _ which maintain their biologic function but are not _ (typically through loss of affinity of the antibiotic for the _)
3) alterations in _ resulting in a decreased ability of the drug to _ and to have _
4) the presence of _ which _ from the cell and hence decrease the amount of drug present at the site of _.
all
enzymes
destroy or inactivate
substitute proteins
targeted by the antimicrobial agent
target site
permeability of bacterial cell
enter the cell
access to its target
pumps
remove antibiotics
antimicrobial action
Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):
There are a wide variety of beta-lactamases.
These enzymes can have either a _ or _-spectrum.
The presence of beta-lactamases is very (common / rare) among pathogens.
Greater than 35% of middle ear isolates of H. influenzae and nearly 100% of M. catarrhalis synthesize a beta-lactamase enzyme rendering these organisms resistant to _.
Another very prominent and prevalent beta-lactamase is the _ enzyme of S. aureus which is found in nearly all strains of this bacterium and emerged shortly after the introduction of _.
narrow
extended
common
amoxicillin
penicillinase
penicillin
Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):
The presence of beta-lactamase enzymes mediate antibiotic resistance through the _ of the _.
As a consequence of this action, the hydrolyzed product is unable to _, one or more of the _, resulting in resistance.
The genes that code for beta-lactamase enzymes may be located on acquired _ or on the bacterial chromosome.
hydrolysis
beta-lactam ring
bind to its target
penicillin binding proteins
plasmids
Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):
Extended spectrum beta-lactamases are an increasingly important class of beta-lactamase enzymes.
These enzymes are notable for their ability to affect _ beta-lactams, including 3rd and 4th generation _.
The genes for ESBLs can be found on _ or they may have been inserted into a _ location.
To date, hundreds of these ESBL enzymes have been reported, many of which have been derived through serial mutations of _ genes.
ESBL enzymes had initially been recovered most frequently from _ and _.
However, these enzymes have now been identified in many other _.
advanced generation
cephalosporins
plasmids
chromosomal
preexisting ESBL
Klebsiella
E. coli
GNR
Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):
An increasing number of broad spectrum beta-lactamases are now recognized.
In addition to ESBLs, a number of bacteria carry _ genes in their chromosomes.
These genes tend to be inducible and can code for (broad / extended)-spectrum beta-lactamase activity which can destroy penicillins and cephalosporins (except for _) and are not fully inhibited by _.
In addition to cefepime, _ are the only beta-lactams that are resistant to hydrolysis by the ampC beta-lactamases.
Finally, the most recent and perhaps most concerning emerging classes of beta-lactamases are the _.
A number of these, related and unrelated, have now been recognized and are being identified with increasing frequency.
ampC
broad
cefepime
beta-lactamase inhibitors
carbapenems
carbapenemases
Development of Altered Targets:
The evolution of altered targets as a mechanism of antibiotic resistance results in a modification of the _ with resultant diminished affinity of the antibiotic for the _ without loss of the target’s _.
Examples of this mechanism of resistance include:
1) alterations in _ leading to beta-lactam resistance
2) the presence of mutant _, resulting in vancomycin-resistance
3) alteration of _ with consequent quinolone resistance
4) alteration of _ resulting in macrolide resistance
antibiotic target
antibiotic target
biologic function
penicillin binding proteins (PBPs)
peptidoglycan precursors
DNA gyrase
ribosome
Development of Altered Targets:
PBPs are found in all _.
The PBP is an enzyme which is responsible for _.
The PBPs covalently bind _; the bound PBP is (able / unable) to perform its essential biologic function causing _.
Antimicrobial resistance occurs through presence of PBPs with (high / low) affinity for beta-lactams which are able to catalyze all steps in _.
This mechanism is responsible for resistance in _, _, and _.
bacterial plasma membranes
cross-linking of cell wall
beta-lactams
unable
cell death
low
cell wall synthesis
S. aureus, E. faecium, and S. pneumoniae
Development of Altered Targets:
A second example is the presence of quinolone resistance secondary to alterations in the enzyme _.
Quinolones exert their antibacterial effect by binding to _ & preventing its normal function.
Mutation of _ gene can be selected by _.
These mutations can result in alterations of _ preventing the _ and hence, conveying resistance.
DNA gyrase
DNA gyrase
DNA gyrase
exposure to quinolones
DNA gyrase
binding of quinolones
Alterations in Permeability of Bacterial Cell:
Alterations in permeability of the bacteria cell impede _, limiting its ability to reach and interact with its site of action.
One of the most common ways that permeability is altered is via mutation or loss of a _.
Porins are proteins that facilitate the _ through the creation of _.
Many antibiotics enter Gram (positive / negative) bacteria via porins.
Modification of porins may prevent or slow _ entrance into cell.
Decreased rates of entrance favors enzymes which _
the entrance of the antimicrobial agent into the bacterial cell
porin
transfer of molecules across cell membranes
“tunnels” that “carry” the molecule from one surface to the other of the bacterial cell membrane
negative
antibiotic
modify antibiotics
Alterations in Permeability of Bacterial Cell:
Modifications of porins play a particularly important role in antibiotic resistance in Pseudomonas aeruginosa.
_ enter P. aeruginosa through a porin known as _.
Decreased expression of this porin results in (enhanced / diminished) permeability of quinolones and other antibiotics into the bacteria.
Alterations in the expression of this porin are easily selected for through the presence of _.
The ease of this selection process accounts in part for the relatively (high / low) prevalence of resistance to quinolones in strains of P. aeruginosa recovered from patients who are treated with quinolones.
Quinolones
OprD
diminished
antibiotic pressure
high
