Details

Autor(en) / Beteiligte

• Papp-Wallace, K. M.
• Mallo, S.
• Bethel, C. R.
• Taracila, M. A.
• Hujer, A. M.
• Fernandez, A.
• Gatta, J. A.
• Smith, K. M.
• Xu, Y.
• Page, M. G. P.
• Desarbre, E.
• Bou, G.
• Bonomo, R. A.

Titel

A kinetic analysis of the inhibition of FOX-4  -lactamase, a plasmid-mediated AmpC cephalosporinase, by monocyclic  -lactams and carbapenems

Ist Teil von

• Journal of antimicrobial chemotherapy, 2014-03, Vol.69 (3), p.682-690

Ort / Verlag

Oxford: Oxford Publishing Limited (England)

Erscheinungsjahr

2014

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Class C β-lactamases are prevalent among Enterobacteriaceae; however, these enzymes are resistant to inactivation by commercially available β-lactamase inhibitors. In order to find novel scaffolds to inhibit class C β-lactamases, the comparative efficacy of monocyclic β-lactam antibiotics (aztreonam and the siderophore monosulfactam BAL30072), the bridged monobactam β-lactamase inhibitor BAL29880, and carbapenems (imipenem, meropenem, doripenem and ertapenem) were tested in kinetic assays against FOX-4, a plasmid-mediated class C β-lactamase (pmAmpC). The FOX-4 β-lactamase was purified. Steady-state kinetics, electrospray ionization mass spectrometry (ESI-MS) and ultraviolet difference (UVD) spectroscopy were conducted using the βlactam scaffolds described. The Ki values for the monocyclic β-lactams against FOX-4 βlactamase were 0.04 ± 0.01 μ (aztreonam) and 0.66 ± 0.03 μM (BAL30072), and the Ki value for the bridged monobactam BAL29880 was 8.9 ± 0.5 μM. For carbapenems, the Ki values ranged from 0.27 ± 0.05 μM (ertapenem) to 2.3 ± 0.3 μM (imipenem). ESI-MS demonstrated the formation of stable covalent adducts when the monocyclic β-lactams and carbapenems were reacted with FOX-4 β-lactamase. UVD spectroscopy suggested the appearance of different chromophoric intermediates. Monocyclic β-lactam and carbapenem antibiotics are effective mechanism-based inhibitors of FOX-4 β-lactamase, a clinically important pmAmpC, and provide stimulus for the development of new inhibitors to inactivate plasmidic and chromosomal class C β-lactamases.