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Medical Microbiology > 17. New antimicrobials for resistant bacteria > Flashcards

17. New antimicrobials for resistant bacteria Flashcards

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1
Q

What infections need new antibiotic treatment?

A
  1. The ESKAPE pathogens.
  2. Particularly healthcare associated ESKAPE infections.
  3. ESBL/carbapenemase-producing Enterobacteriaceae and pan-resistant non fermenters.
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2
Q

How do the WHO classify priority pathogens?

A
  1. Critical
  2. High
  3. Medium
  4. Includes mostly GI pathogens and community pathogens from lower-income countries
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3
Q

What kind of pathogens are WHO critical?

A
  1. Carbapenem resistant bacteria P.aeruginosa and A. baumannii
  2. Carbapenem and ESBL resistant enterbacterales
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4
Q

What is the current status of antibiotic discovery?

A
  1. 43 drugs in various stages of discovery from phase 1 trials to almost in clinic.
  2. It is most made up of ß-lactams and ß-lactamase inhibitors.
  3. Basically, there are no novel treatments for gram negatives and very few for gram positives.
  4. This is a lack of innovation compared to other sectors.
  5. At the same time there were 1300 oncology drugs in development.
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5
Q

Do the new drugs in development cover all challenging resistant pathogens?

A

No not really and the ones that do are just variations on existing drugs.

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6
Q

Why are unused antibiotic targets not being developed further?

A
  1. There are lots of problems with them.
  2. Struggled to find a single effective drug from this approach.
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7
Q

What antibiotic targets that we know could be developed further?

A
  1. Anything that targets more than one molecule and can be targeted by multiple antibiotics.
  2. This includes PBPs and topoisomerases.
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8
Q

How could we develop multi target activity antibiotics?

A
  1. Finding new drugs
  2. Making existing drugs better.
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9
Q

What new antibiotic therapy has been very effective?

A

Inhibitors like ß-lactamase inhibitors

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10
Q

What needs to be overcome to discover new treatments for gram negatives?

A

The gram-negative permeability barrier.

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11
Q

What other methods of new antibiotic therapy are there?

A
  1. Combination therapy of antibiotics. This is used a lot for other things like cancer but not really used for bacterial infections.
  2. Narrow-spectrum agents. This gets around problems with broad-spectrum activity but requires better diagnostic techniques.
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12
Q

How were proven targets used to develop antibiotic treatments for MRSA?

A
  1. MRSA is resistant to ß-lactams by using a PBP2 analogue PBP2a.
  2. Once the structure of PBP2a was discovered we could design a specific ß-lactam to target it.
  3. This was the cephalosporin ceftaroline.
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13
Q

How was the structure of ceftaroline different from other ß-lactams?

A

Carbon 3: There is a pyridine ring and a thiazole ring to help it fit into the PBP2a active site.
Carbon 7: This is similar to the other ß-lactams but provides resistance to ß-lactamases and improves solubility.

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14
Q

How does ceftaroline work?

A
  1. It binds at an allosteric site to open up the PBP2a active site.
  2. It does this through a series of conformational changes that allows ceftaroline to enter the active site.
  3. This mode of action was only established after more analysis of how the drug interacts with the target.
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15
Q

What are the 2 ways new ß-lactams can be developed?

A
  1. Using existing scaffolds of ß-lactams
  2. Exploit ß-lactamase inhibitors that don’t use the ß-lactam scaffold
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16
Q

How does avibactam work?

A
  1. It is a reversible inhibitor.
  2. It covalently binds with high affinity to the ß-lactamase serine.
  3. Although the binding is high affinity, it is reversible.
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17
Q

What can you develop from ß-lactamase inhibitors?

A

New antibiotic compounds

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18
Q

Why can you develop new antibiotics from ß-lactamase inhibitors?

A

The ß-lactamase inhibitors targets the ß-lactamase active site serine so it could target the PBP active site serine.

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19
Q

How were new antibiotics developed from ß-lactamase inhibitors?

A
  1. The DBO scaffold was enhanced so it could bind PBPs.
  2. There were a series of chemical modifications at positions R1, R2, and R3.
  3. It showed efficacy comparable to the control antibiotic.
  4. It looks really good but the future is uncertain due to money and politics.
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20
Q

What chemical properties did the different chemical modifications of DBO do?

A

R1 = affects PBP selectivity and permeation
R2 = potency and solvency
R3 = For carbapenem binding
R4 = Acid group required for binding in the PBP pocket

21
Q

How can old antibiotic targets produce new drugs?

A

by targeting them with new mechanisms

22
Q

How can PBPs be targeted in a new way?

A
  1. By targeting the transglycosylation activity of high molecular weight PBPs.
  2. There are known natural products that do this.
  3. However turning these into useful antibiotics is challenging.
23
Q

Why is targeting the transglycosylation domain of PBPs tricky?

A

This is because they sit at the membrane and act on membrane-bound substrate.

24
Q

What is Vaborbactam?

A
  1. A boron based ß-lactamase inhibitor.
  2. It makes a tetrahedral structure around the boron atom that mimics the tetrahedral transition state associated with the ß-lactamase reaction.
25
Q

What does vaborbactam inhibit?

A
  1. Class A and C ß-lactamases
  2. so used to treat carbapenem-resistant enterobacterales along with meropenem
26
Q

What is taniborbactam?

A
  1. A bicyclic boron based ß-lactamase inhibitor.
  2. It can inhibit serine ß-lactamases by binding with the active site serine.
  3. Can also mimic the tetrahedral structure formed by metallo ß-lactamases and inhibit them.
27
Q

Why are cross-class inhibitors like taniborbactam so promising?

A

They are the only inhibitors near the clinic that are active against metallo ß-lactamases like NDM-1

28
Q

What else has good potential to target with new antibacterials?

A
  1. Type 2 topoisomerases
  2. Fluoroquinolones target these
  3. Lots of known natural products targets type 2 topoisomerases.
29
Q

What is gepotidacin?

A
  1. It has a similar structure to quinolones and looks like it mimics DNA.
  2. It has a planer structure that intercalates with DNA.
30
Q

What are the 2 mechanistic differences between fluoroquinolones and gepotidacin?

A
  1. It introduces ssDNA breaks into the DNA when fluoroquinolones introduce dsDNA breaks.
  2. Only 1 molecule is needed to bind to the topoisomerase whereas 2 fluoroquinolones are needed.
31
Q

What could gepotidacin be used to treat?

A
  1. fluoroquinolone resistant infection.
  2. Gepotidacin has a different binding site so is not effected by mutations in the quinolone resistance determining region.
32
Q

What else is gepotidacin effective against?

A
  1. N. gonorrhoeae
  2. It is very potent
  3. It has reached the end of phase 3 trials and is likely to make it to clinic in 2025
33
Q

How can topoisomerases be targeted in new ways?

A

by using other natural or synthetic drugs that bind in different ways and generate antibiotic activity differently

34
Q

What does an antibiotic need to do to get into a gram negative bacteria?

A
  1. Get through a porin in the outer membrane. They need to small and hydrophilic to do this.
  2. Then they need to get through the inner membrane and need to be hydrophobic to do this.
35
Q

How can problems with gram negative barrier permeability be overcome?

A
  1. By finding targets in the periplasm like PBP or LPS synthesis.
  2. Hijack their normal physiological uptake mechanisms to get the antibiotic into the cell.
  3. Find a set of rules like the Lipinski rules for bacteria targeting drugs.
  4. Could inhibit efflux but this is hard and unrealistic.
36
Q

What antibiotic was developed that can hijack gram-negative uptake mechanisms?

A

Cefiderocol

37
Q

What is cefiderocol?

A
  1. A ß-lactam that can enter gram negative bacteria using their iron uptake mechanism.
  2. An important addition to gram negative treatment
38
Q

How does Cefiderocol enter the gram negative bacteria?

A
  1. This existing ß-lactam scaffold was modified to exploit the iron uptake mechanism.
  2. This is done through a catechol moiety.
  3. also stable against ß-lactamases
39
Q

How does iron uptake normally work in gram negative bacteria?

A
  1. A small catechol molecule binds to iron in the environment.
  2. It then brings it back into the periplasm through a specific uptake system then dissociates.
40
Q

How does the catechol moiety work to bring cefiderocol into the bacteria?

A
  1. It is attached to the antibiotic and then taken up through the normal mechanisms.
  2. dissociates in the periplasm
  3. Then can target PBPs and evade ß-lactmases.
41
Q

What is the problem with using the bacteria’s own uptake mechanisms?

A
  1. It is vulnerable to resistance.
  2. The bacteria can just mutate and change the system.
  3. This has occasionally been seen to cefiderocol
42
Q

What chemical properties are associated with uptake into gram negative bacteria?

A
  1. Rigid
  2. Planer
  3. With few rotatable bonds
  4. Low globularity
  5. A free amine group
43
Q

How do we know a free amine group is important for gram negative antibiotic uptake?

A
  1. Ampicillin and amoxicillin were the first ß-lactams that could treat gram negative infections.
  2. These both have a free amine group.
44
Q

Could you take a gram positive treating antibiotic and modify it to treat gram negative infections?

A
  1. Yes
  2. If you alter them in the context of these “rules”
45
Q

How was a FabI inhibitor altered to help it get into a gram negative bacteria?

A
  1. It had most of the desirable properties anyway.
  2. They added a free amine group, which allowed them to enter gram negative cells.
  3. It also still retained most of its ability to treat gram-positive infections as well.
46
Q

How did AI contribute to the modifying of the FabI inhibitor?

A
  1. The researchers made an algorithm that was educated on large datasets of molecules with antimicrobial activity and molecules that didn’t.
  2. Then, the AI searched libraries of molecules and found molecules with similar chemical properties to known antimicrobial compounds.
  3. The research took the top 100 potential Antimicrobials, and 50 worked.
47
Q

How is AI being used to find new antibacterial?

A
  1. A research group used a similar model that had been educated on antibacterial properties.
  2. Screened the ZINC15 database which contains over 1 billion molecules.
  3. This was too many to screen so restricted it to 107 million
  4. They then tested the top 23 results and 8 were antibacterial.
  5. Lots of new paper and research using AI but nothing has made it to the clinic yet.
48
Q

What is the need for new antibiotics driven by?

A

The emergence and dissemination of resistance.

49
Q

What are new antibacterial most crucial for?

A

Pan-resistant gram negatives

Medical Microbiology (17 decks)

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