title: NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against beta-lactamase-producing strains.
abstract: Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. beta-Lactamase overexpression is a common mechanism of bacterial resistance to beta-lactam antibiotics. We present here the results for one of the beta-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional beta-lactam antibiotics, where hydrolysis of the beta-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by beta-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 beta-lactamase, forming triclosan with a second-order rate constant (k(cat)/K(m)) of greater than 77,000 M-1 s-1. (ii) Triclosan is detected in NB2001-treated, beta-lactamase-producing Escherichia coli but not in E. coli that does not express beta-lactamase. (iii) NB2001 activity against beta-lactamase-producing E. coli is decreased in the presence of the beta-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 beta-lactamase-mediated resistance.
authors.affiliation: NewBiotics, Inc., San Diego, California 92121, USA. qli@newbiotics.com
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Rosario
authors.initials: R
authors.lastname: Castillo
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hixon
authors.forename: Catherine
authors.initials: C
authors.lastname: Pujol
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Doppalapudi
authors.forename: H Michael
authors.initials: HM
authors.lastname: Shepard
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lobl
authors.forename: Ming Fai
authors.initials: MF
authors.lastname: Chan
mesh_terms: D001424:Bacterial Infections / Q000382:microbiology; D002511:Cephalosporins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014260:Triclosan / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D002511:Cephalosporins; C461664:NB 2001; D011355:Prodrugs; D014260:Triclosan; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1