Article notes - Antimicrobial resistance Flashcards
Make the case that antimicrobial resistance is a significant concern
Antimicrobial resistance has become an epidemic, causing many annual deaths. It targets countries with poor public health, hospitals, long-term facilities with vulnerable patients that have a weakened immune system like cancer patients, diabetics, premature newborn, or surgical patients
List at least five factors that have contributed to this problem
Factors that have contributed to this problem of antibiotic resistance goes as follow: over-prescription, widespread use of antibiotics for growth promotion in agriculture, reliance
on broad-spectrum treatment, the innovation gap between antibiotic research and development, and evolution of bacteria
Describe the most common (standard) assay that has historically been used to determine the effectiveness of a given antibiotic against a particular bacterial strain
what is it called?
Minimum inhibitory concentration
Describe the most common (standard) assay that has historically been used to determine the effectiveness of a given antibiotic against a particular bacterial strain
How is it done?
MIC has bacteria grown in either Mueller-Hinton broth or agar where it has
increasing concentrations of the antibiotic and what they are testing for is the
presence or absence of the bacteria
Describe the most common (standard) assay that has historically been used to determine the effectiveness of a given antibiotic against a particular bacterial strain
How is it interpreted? Why?
MIC is determined by observing the bacterial growth. The colored wells show bacterial growth, while the clear wells show the inability for bacterial growth to form in the classical antibiotics that are tested. Row A yields clear walls through column 10, while row B only yields clear walls through column 7, and this shows a difference in MICs. Row A’s antibiotics works more efficiently at limiting the bacterial growth at a lower concentration rate than row B’s antibiotics, as row B can only limit at column 7 antibiotic concertation, unlike row A
If the compound in row F has therapeutic properties, why are none of the wells clear?
Row F does not have clear wells as it goes undetermined by the MIC assay. Row F is an immune sensitizer, and it is a type of antibacterial that operates at the host-pathogen level and thus is unidentified by the MIC assay, resulting in colored wells
What are some of the problems with this assay?
The problems with MIC assay is that it is outdated and it only identifies direct killing and growth suppression, but there’s different types of antibacterial MOA, which can be virulence blockers, immune sensitizers, and immune boosters. These MOA go unnoticed
by the MIC assay, and MIC assay is limited to only classical antibiotics
Describe a virulence blocker. How does it behave differently than a “classical” antibiotic?
Virulence blockers do not directly affect bacterial growth like a classical
antibiotic, they inhibit a particular virulence factor. They do not kill the bacterium, but they make it harmless
What are “nanosponges?” How do they work?
Nanosponges are a concept designed to inactivate S. aureus alpha-toxin and other
toxins without direct action. They are made of biodegradable nanoparticle and are coated by the cell membrane of the host cell; they replicate the target of the toxin. Nanosponges act as a decoy to bind the toxins and stray them away from the host cell.
Describe two examples of situations in which these may be useful
Two situations where virulence blockers can be useful is at with bacterial sepsis and S. aureus infections. S. aureus infections, like pneumonia, can be treated using nanosponges made from red blood cells of O-negative blood as it can help
neutralize the alpha-toxin and limit lung damage. For bacterial sepsis with E.coli,
macrophage nanosponges are useful as they capture the bacterial pore-forming
toxin, which helps reduce damage to host cells, they bind to the endotoxin to
reduce activation of LBP-CD14-TLR4 signaling, and they scavenging excessive
proinflammatory cytokines that cause cytokine storm and multiorgan failure.
Describe an immune sensitizer. How does it behave differently than a “classical” antibiotic?
Immune sensitizers are different than classical antibiotics as classical antibiotics directly kill and prevent bacterial growth, while immune sensitizers produce antimicrobial peptides, which are made by our epithelial cells. These AMPs have bactericidal activities, and they are positively charged which attracts negatively charged bacterial surfaces and thus they can insert themselves into the bacteria and cause bacterial lysis and death
What is a cathelicidin?
A cathelicidin is a part of the AMPs family and has antimicrobial properties
against various pathogens. Human cathelicidin has immunomodulatory roles that recruit and activate host defenses.
Provide two examples of situations in which an immune sensitizer may be useful. Why? (What is happening?) Are the bacteria Gram positive or Gram negative?
Immune sensitizer may be useful in the treatment with methicillin-resistant
staphylococcus aureus, which even with low doses of nafcillin, it increases the
susceptibility of MRSA to killing LL-37. These are MDR gram positive bacteria
that methicillin-resistant staphylococcus aureus is used for, and it can be
correlated to the increase binding of LL-37 to the bacterial cell in bacteria that are exposed to nafcillin. Another example is azithromycin, which is a treatment for MDR gram negative pathogens, and when AZM is combined with LL-37 the MDR gram negative bacterial strain was killed. There is an increase entry of AZM in the bacterial cell with LL-37
Why is drug repurposing preferable to novel drug discovery?
Drug repurposing is preferable to novel drug discovery because it has lower risk failure since the drug is known to be safe for humans, it also has a shortened development time, less investment and familiarization of the drug makes it easier to prescribe them
Briefly describe the conflict between Staphylococcus aureus and blood platelets
The conflict between S. aureus and blood platelets is that blood platelets are more
efficient at killing S. aureus than neutrophils, yet S. aureus bring the bloods
platelets down due to its secretion of alpha-toxin, because it includes cytotoxicity in platelets.
