KPC-2 Carbapenemase
A class A serine carbapenemase from Klebsiella pneumoniae — the enzyme behind much of the world's carbapenem-resistant Enterobacteriaceae (CRE) burden. Analysed end-to-end by the ResistAI pipeline.
Protein overview
Clinical significance
KPC-2 is the most globally disseminated carbapenemase, hydrolysing virtually all β-lactams including carbapenems — the last-resort agents for serious Gram-negative infections. Unlike metallo-β-lactamases (e.g. VIM, NDM), KPC-2 uses a serine-based catalytic mechanism, which makes it susceptible to the β-lactamase inhibitor avibactam. Ceftazidime-avibactam is now a frontline therapy against KPC-producing strains — though resistance via KPC point mutations is already emerging, keeping this an active drug-discovery target.
Druggability analysis — fpocket
Note: Druggability scores are structural proxies computed by fpocket on AlphaFold-predicted structures (Le Guilloux et al. 2009). Thresholds: high ≥ 0.7, medium ≥ 0.4. Experimental validation is required to confirm binding site tractability.
Interpretation
fpocket identified 17 surface cavities in the AlphaFold-predicted KPC-2 structure, with a top pocket score of 0.427 (medium druggability). This is a biologically honest result: KPC-2's active site is a relatively shallow, solvent-exposed serine cleft — harder to target with conventional small molecules than a deep hydrophobic pocket. This is precisely why clinically successful inhibitors like avibactam are covalent, diazabicyclooctane-based agents rather than classical competitive binders. The medium structural score, read alongside the literature, captures a real pharmacological challenge rather than overstating tractability.
ESM-2 embedding similarity
480-dim cosine similarityESM-2 (esm2_t12_35M_UR50D) generated a 480-dimensional sequence embedding for KPC-2. ChromaDB cosine similarity search identified the five most evolutionarily related proteins in the 2,433-protein database — all class A serine β-lactamases from Enterobacteriaceae, confirming the biological coherence of the embedding space.
Klebsiella oxytoca
Klebsiella oxytoca
Klebsiella oxytoca
Escherichia coli
Yersinia enterocolitica
Key finding: All five nearest neighbours are class A serine β-lactamases from Enterobacteriaceae, with cosine similarities of 0.98–1.00. Notably, the embedding groups KPC-2 with other serine enzymes rather than with metallo-β-lactamases like VIM or NDM — mirroring the true mechanistic divide between the two carbapenemase classes, captured from sequence alone.
Relevant resistance literature
Klebsiella pneumoniae Carbapenemase Variants Resistant to Ceftazidime-Avibactam: an Evolutionary Overview
Antimicrob Agents Chemother · 2022
Assessment of the activity and mechanisms of resistance to cefiderocol and combinations of β-lactams and novel β-lactamase inhibitors in carbapenemase-producing Enterobacterales
Antimicrob Agents Chemother · 2024
Emerging resistance to novel β-lactam β-lactamase inhibitor combinations in Klebsiella pneumoniae bearing KPC variants
J Glob Antimicrob Resist · 2025
Multiple mechanisms mediate aztreonam-avibactam resistance in Klebsiella pneumoniae: Driven by KPC-2 and OmpK36 mutations
Int J Antimicrob Agents · 2025
Pipeline summary
UniProt ID Q9F663 resolved — sequence and metadata fetched via UniProt REST API
3D structure retrieved from AlphaFold DB (high-confidence predicted model)
fpocket detected 17 binding cavities — top pocket scored 0.427 (medium druggability)
ESM-2 generated 480-dim sequence embedding — ChromaDB similarity search returned 5 serine β-lactamase homologs (similarity 0.98–1.00)
RAG retrieved 4 directly relevant PubMed articles on KPC-2 / ceftazidime-avibactam resistance
Llama 3.3 70B synthesised a PMID-cited research summary contextualising the druggability assessment