TECHNOLOGYAntimicrobial Heme Oxygenase Inhibitors and Methods of Use
Overview
Antimicrobials are widely used to treat a variety of infections. However, due to overuse and microbial evolution, many antimicrobials are rendered ineffective as first-line therapies. This invention is a new class of broad-spectrum, small-molecule antimicrobials that target the critical enzyme, heme oxygenase that is required to process heme, an iron carrying small molecule. The inhibition of heme oxygenases could be used for the treatment of microbial infections.
Iron acquisition is a critical function for bacterial pathogens for survival and virulence. Heme oxygenases are required to cleave heme to yield biliverdin, iron, and carbon monoxide. The discovery of heme oxygenase inhibitors offers a novel target and the potential for the development of a new class of antimicrobial agents with broad-spectrum activity. These inhibitors were identified using a computer-aided drug design (CADD) screening approach combined with experimental assays to identify small-molecule inhibitors of the Neisseria meningitides HO (nm-HO). Several of the compounds were shown to have KD values in the micromolar range for nm-HO and the Pseudomonas aeruginosa HO (pa-HO). The compounds also inhibited the growth of P.aeruginosa as well as biliverdin formation in E. coli cells overexpressing nm-HO. Thus, CADD combined with experimental analysis has been used to identify novel inhibitors of the bacterial heme oxygenases that can cross the cell membrane and specifically inhibit HO activity.
Applications
Nearly 2 million patients in the United States get an infection in the hospital each year and about 90,000 of those patients die as a result of their infection. More than 70 percent of the bacteria that cause hospital-acquired infections are resistant to at least one of the antibiotics most commonly used to treat them. The continuous evolution of bacterial pathogens and the resulting development of drug resistance creates a constant need for the development of new antibiotics. To encourage development the Generating Antibiotics Incentives Now Act (GAIN Act) was passed to potentially provide expedited review and an additional five years of exclusivity for antibiotic and antifungal drugs that qualify. Between the years 2010 – 2015, the U.S. Food and Drug Administration (FDA) has approved eight new antibiotics: ceftaroline, fidaxomicin, bedaquiline, dalbavancin, tedizolid, oritavancin, ceftolozane-tazobactam, and ceftazidime-avibactam. However, seven had similar mechanisms of action to those of previously approved drugs.
Advantages
- New target
- Broad-spectrum antimicrobial properties
- Small molecule
- Permeability
- Blood-brain permeability
- Reduced immune response
- Enhanced stability
- Decreased biomaterial contamination potential
- Capacity for large-scale manufacturing
Stage of Development
Small molecules possessing antimicrobial properties have been identified.
R&D Required
Lead compound optimization. Studies are required to demonstrate efficacy and safety prior to use in human subjects.
Licensing Potential
UM seeks to develop and commercialize by an exclusive or non-exclusive license agreement and/or sponsored research with a company active in the area.
Contact Info
Office of Technology Transfer
620 W Lexington St., 4th Floor
Baltimore, MD 21201
Email: [email protected]
Phone: (410) 706-2380
