NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against β-lactamase-producing strains
In: Antimicrobial agents and chemotherapy, Jg. 46 (2002), Heft 5, S. 1262-1268
Online
academicJournal
- print, 32 ref
Zugriff:
Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. β-Lactamase overexpression is a common mechanism of bacterial resistance to β-lactam antibiotics. We present here the results for one of the β-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional β-lactam antibiotics, where hydrolysis of the β-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by β-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 β-lactamase, forming triclosan with a second-order rate constant (kcat/Km) of greater than 77,000 M-1s-1. (ii) Triclosan is detected in NB2001-treated, β-lactamase-producing Escherichia coli but not in E. coli that does not express β-lactamase. (iii) NB2001 activity against β-lactamase-producing E. coli is decreased in the presence of the β-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of Staphylococcus aureus (including MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Moraxella catarrhalis and Haemophilus influenzae. NB2001 is also active against Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming β-lactamase-mediated resistance.
Titel: |
NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against β-lactamase-producing strains
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Autor/in / Beteiligte Person: | QING, LI ; LEE, Jean Y ; CASTILLO, Rosario ; HIXON, Mark S ; PUJOL, Catherine ; DOPPALAPUDI, Venkata Ramana ; SHEPARD, H. Michael ; WAHL, Geoffrey M ; LOBL, Thomas J ; MING FAI, CHAN |
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Zeitschrift: | Antimicrobial agents and chemotherapy, Jg. 46 (2002), Heft 5, S. 1262-1268 |
Veröffentlichung: | Washington, DC: American Society for Microbiology, 2002 |
Medientyp: | academicJournal |
Umfang: | print, 32 ref |
ISSN: | 0066-4804 (print) |
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