B-Lactams Medchem

Question 1

PCN Pharmacores

Answer 1

• Angles are close to 90 degrees
• sp3 want angles at ~109 degrees and sp2 want 120 degrees
• Leaves the 4 membered ring with great strain
• Very reactive

Question 2

PCN Ring Formation

Answer 2

• Condensation to form an amide bond
• Unstable in water (bad)
• Reactive with other nucleophiles as well which is the basis of its action
• Ring puts them closer to transition state compared to a linear amide

Question 3

Beta Lactam Formation Options

Answer 3

1. Biosynthetically by fermentation (common)

2. Synthetically (rare), hard to do, used for some monobactams

Question 4

Biosynthetic Formation

Answer 4

• Non-ribosomal peptide synthetase

- B lactam synthetases use energy from oxidation or ATP to cyclize, then various modifications are added

Question 5

PCN Target

Answer 5

• Irreversibly bind to bacterial enzyme penicillin-binding transamidase
• Makes the peptidoglycan layer in Gram “+” and “-“ bacteria
• Activated B lactam forms an ester (relatively stable) with a serine hydroxyl group at the active site of transamidase which is irreversible and stops cell wall formation
• The PBP targets performs a kind of stereochemistry that doesn’t occur in mammals, why it is safe to give to humans (D-amino acids are rare)
• Binding of the PCN to the enzyme creates steric and charge repulsion factors that helps stop the cell wall synthesis

Question 6

PCN + Acid

Answer 6

• Unstable in acid which can limit its oral efficacy
• Oxygen attacks pencillin’s amide to produce lactone which hydrolyzes to create a penicilloic acid intermediate
• This acid intermediate will then undergo spontaneous decarboxylation which is irreversible

Question 7

Mold Utilization

Answer 7

• Makes lactam core first, then add different groups with the last being an amide
• Incorporate an excess of a compound in the medium growing the mold and lead to creations of different penicillins
• Phenylacetic acid => benzylpenicillin (strong nucleophile)
• Phenoxyacetic acid => phenoxymethylpenicillin

Question 8

Reactivity + Allergic Reaction

Answer 8

• Same reactivity causes reaction with host protein serine residues
• Forms penicillin-protein conjugate which antibodies are formed against

Question 9

Beta Lactamase Resistance

Answer 9

• B lactamase opens the lactam ring, making it unbindable with PBP
• Leads to bacterial resistance against B-lactams

Question 10

Fetroja

Answer 10

• New cephalosporin
• Mimics siderophore (iron binding molecule used by bacteria to acquire iron)
• Actively taken up by some Gram “-“ bacteria

Question 11

Lactamase Inhibitors

Answer 11

• Activated by lactamase
• Inhibit some beta lactamase to act synergistically with beta lactams and increase their scope of coverage
• “Dual anchor” system to prevent lactamase reactivation
• Cleavage create reactive protein which reacts with beta lactamase since it is the first thing it sees

Question 12

Newer BLI Combinations

Answer 12

1. AVYCAZ: avibactm + another cyclic amide

2. Vabomere: meropenem/vaborbactam, brod based inhibitor, covalent bonds serine

Question 13

Summary

Answer 13

• Beta lactam is high energy reactive cyclic amide
• Covalent bonds to PBP inhibits peptidoglycan cross linking and weak cell walls
• Acid resistance is achieved by limiting electron density or internal O nucleophile
• Covalent binding to host proteins lead to allergic reactions
• Bacterial lactamases cleave lactam and cause bacterial resistance to Abx
• Lactamases and unique inhibitors can overcome the resistance by covalent inhibition of lactamase