Development of Novel Inhibitors of New Delhi Metallo-beta-lactamase-1 (NDM-1)
- 技术优势
- This invention represents a major discovery because there are currently no approved drugs to block NDM-1. These discoveries could lead to development of new therapeutics to treat these highly pathogenic and resistant bacteria.
- 技术应用
- The new inhibitors for NDM-1 are targeted toward the very pathogenic multidrug-resistant bacteria such as carbapenem-resistant Enterobacteriacae and Klebsiella pneumoniae.
- 详细技术说明
- Researchers at UC San Diego have successfully designed and synthesized a new class of inhibitors for New Delhi Metallo-betalactamase-1 (NDM-1) and two related beta-lactamases. They exhibit remarkable selectivity as they don’t hit other Zn(II) metalloenzymes. The inhibitors restored susceptibility to imipenem in three different E.coli strains, including a clinical isolate expressing blaNDM-1.
- *Abstract
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Antibiotic-resistance in pathogenic bacteria has become a critical public health threat. A major mechanism of antibiotic resistance is microbial degradation of drugs by enzymes such as β-lactamases which degrade the β-lactam ring of β-lactam antibiotics, namely penicillins, cephalosporins, carbapenems and monobactams, inactivating them. There are four different molecular classes of β-lactamases (A-D). Three classes of β-lactamases (A, C, and D) utilize an active-site serine in covalent mechanisms that can be targeted by β-lactamase inhibitors coformulated with β-lactam drugs. In contrast, class B consists of metallo-β- lactamases (MBLs) that utilize one or two active site Zn(II) ion(s) to catalyze the hydrolysis of the β-lactam ring. The emergence of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1) and its variants, worldwide, has raised a major public health concern. NDM-1 hydrolyzes a wide range of β-lactam antibiotics, imipenem, meropenem, ertapenem, gentamicin, amikacin, tobramycin, and ciprofloxacin including carbapenems, which are the last resort of antibiotics for the treatment of infections caused by multidrug-resistant bacteria such as carbanenem-resistant Enterobacteriacae and Klebsiella pneumoniae. Currently, there are Inhibitors of NDM-1, both of which have liabilities, either due to adverse effects in mammals or off-target inhibitory activity. Therefore, a new type of NDM-1 inhibitor is needed.
- *Principal Investigation
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Name: Robert Bonomo
Department:
Name: Michael Crowder
Department:
Name: Walter Fast
Department:
Name: David Tierney
Department:
Name: Yingyao Allie Chen
Department:
Name: Seth Cohen
Department:
- 其他
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State Of Development
The inventors have used a fragment-based drug discovery platform to identify a new class of inhibitors for NDM-1 and two related B-lactamases. The inhibitors were found to be highly selective for metallo-β-lactamases when compared to other Zn(II) metalloenzymes.
Intellectual Property Info
A provisional patent has been submitted and the technology is available to license.
Related Materials
Tech ID/UC Case
29251/2017-259-0
Related Cases
2017-259-0
- 国家/地区
- 美国
