SBIR-STTR Award

The goal of this project is to determine the feasibility of developing inhibitors of the Staphylococcus aureus multidrug-efflux transporter NorA. NorA provides S. aureus with intrinsic resistance to fluoroquinolone antibiotics by reducing their concentration inside the bacterial cell. Inhibition of NorA has been demonstrated to dramatically potentiate the antibacterial action of fluoroquinolones and prevent the emergence of antibiotic-resistant variants of S. aureus. One NorA inhibitor 1 reserpine, has already been identified by the authors. Unfortunately, the use of reserpine is limited by its neurotoxicity. Preliminary studies have demonstrated that reserpine is not unique in its ability to inhibit NorA; screening of 2,500 organic compounds has yielded a number of structurally diverse molecules also capable of suppressing NorA activity. During the first, exploratory phase of the project, 7,500 more compounds will be screened for their ability to inhibit NorA. To eliminate toxic compounds, the identified inhibitors will be tested for their toxicity to a panel of human cell lines. The compounds to which NorA can become insensitive through mutations will also be eliminated. The remaining inhibitors of highest potency will be used in Phase Il of the project as lead compounds, on the basis of which we expect to develop a clinically useful NorA inhibitor. PROVIDE COMMERCIAL APPLICATIONS This project is to develop nontoxic inhibitors of the S. aureus multidrug transporter NorA, the protein involved in resistance of these bacteria to fluoroquinolone antibiotics. The envisioned commercial product is a combination of such an inhibitor with fluoroquinolone. Given that staphylococcal infections are widespread and rapidly become resistant to antibiotic therapy, the market for this product is likely to be comparable to the market for major antibiotics.

Thesaurus Terms:
Staphylococcus aureus, antibiotic, drug design /synthesis /production, inhibitor /antagonist, multidrug resistance, transport protein reserpine Bacillus subtilis, microorganism culture, tissue /cell cultureNational Institute of General Medical Sciences (NIGMS)

The goal of this Phase II SBlR project is to develop clinically useful inhibitors of the multidrug-efflux transporters of the Gram positive pathogens, Staphylococcus aureus and Streptococcus pneumoniae. These transporters are partially responsible for the i ntrinsic and acquired resistance of these bacteria to fluoroquinolone antibiotics. Preliminary results demonstrate that inhibition of the multidrug transporters would dramatically increase the effectiveness of fluoroquinolone therapy by both increasing the intrinsic susceptibility of these pathogens to fluoroquinolones and suppressing the emergence of drug-resistant variants. In the ongoing Phase I SBIR project we screened a library of synthetic chemicals and identified several very promising lead compounds that effectively inhibit the S. aureus multidrug transporter NorA and the presently unidentified multidrug transporter of pneumoniae. Here we propose to optimize the properties of lead inhibitors through several cycles of improvement, each involving synthes is of structural analogs of the leads, biological evaluation of their activity and toxicity, and QSAR analysis. The improved inhibitors will be thoroughly characterized, including preliminary toxicology studies. The obtained results will eventually allow us, in alliance with a large pharmaceutical company, to develop a potent combination antimicrobial drug containing a fluoroquinolone and an inhibitor of multidrug transporters. PROPOSED COMMERCIAL APPLICATIONS: The project is to develop broad spectrum inhibitors of multidrug transporters providing resistance to fluoroquinolone antibiotics in Gram positive pathogens. Patents will be applied for the improved inhibitors before licensing to a pharmaceutical company. The envisioned commercial product is a combination of such an inhibitor with a fluoroquinolone antibiotic.

Thesaurus Terms:
P glycoprotein, antibiotic, drug design /synthesis /production, drug screening /evaluation, inhibitor /antagonist, multidrug resistance Staphylococcus aureus, Streptococcus pneumoniae, antibacterial agent, chemical structure /function, chemical substitution, conformation, drug adverse effect, drug interaction, reserpine HeLa cell, chemical information system, chemical synthesis, laboratory rat, microorganism culture, nuclear magnetic resonance spectroscopy, tissue /cell cultureNATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES