Antimicrobial Resistance & β-Lactamase Inhibitors

What is the primary biological target of β-lactam antibiotics like penicillin?

Transpeptidase enzymes (Penicillin-Binding Proteins or PBPs) that catalyse the cross-linking of peptidoglycan in the bacterial cell wall.

What specific part of the peptidoglycan structure do PBPs recognise and cleave?

The terminal D-Ala-D-Ala motif of the peptide side chain.

What is the key structural feature of all β-lactam antibiotics that is essential for their activity?

The strained, four-membered β-lactam ring.

What are the four main mechanisms bacteria use to resist β-lactam antibiotics?

1) Produce β-lactamases, 2) Mutate the PBP target, 3) Reduce permeability (porins), 4) Upregulate efflux pumps.

Why are MBLs considered a "hard target" for drug design?

Shallow active site, lack of conserved amino acids directly involved in catalysis, and the challenge of targeting a zinc-dependent mechanism without causing off-target toxicity.

What is the core function of a β-lactamase inhibitor

To act as a "shield" for a co-administered antibiotic by inhibiting the β-lactamase enzyme, protecting the antibiotic from destruction.

What is a key medicinal chemistry reason for clavulanic acid resistance, e.g., in TEM-1?

Mutations (like Arg244Ser) that disrupt critical salt bridge/ionic interactions in the enzyme's active site, reducing inhibitor binding.

What is the primary medicinal chemistry advantage of DBOs like avibactam?

Their bulky, three-dimensional shape hinders the deacylation process in SBLs, and they inhibit a broader spectrum (Classes A, C, D).

Name two drug repurposing candidates for MBL inhibition and their original use.

Captopril (an ACE inhibitor for hypertension) and Dimercaprol (an antidote for heavy metal poisoning).

Why is using a chelator like EDTA a problematic strategy for inhibiting MBLs in patients?

Lack of specificity. It chelates essential ions like Zn²⁺, Ca²⁺, and Mg²⁺, disrupting human metalloproteins and causing systemic toxicity (e.g., hypocalcaemia).

What is the primary chemical difference between the inhibition mechanisms of clavulanic acid and avibactam?

Clavulanic acid is an irreversible, mechanism-based inactivator that ultimately destroys the enzyme. Avibactam is a reversible covalent inhibitor that does not permanently inactivate it.

What is an "oxyanion hole" and what is its role in PBP/β-lactamase function?

A pocket in the enzyme active site that stabilises the negative charge on the oxygen atom in the tetrahedral transition state intermediate during catalysis.

What does SBL stand for, and what is its catalytic residue?

Serine β-Lactamase. It uses an active-site Serine residue as a nucleophile.

What does MBL stand for, and what is its key catalytic component?

Metallo-β-Lactamase. It uses one or two Zn²⁺ ions to activate a water molecule (OH⁻) as the nucleophile.