In 2002 the number of Healthcare-Associated Infections (HAIs) in the U.S. was estimated at 1.7 million with nearly 100,000 related deaths. Although progress has been reported, an estimated 1.3 million patients were forecast to contract an HAI in 2020. Estimated total annual costs for the five major HAIs were $6.89 billion when Multi-drug Resistant Staphylococcus Aureus and Clostridium difficile infections were excluded. About 45% of HAIs (~0.5 million) are caused by Gram-negative bacteria where antibiotic resistance is a major unmet medical need.
RND Efflux Pump Gram-negative bacteria that have evolved or acquired active and/or passive resistance mechanisms have been reported against essentially all commercially available antibiotics. A principal mechanism by which such bacteria resist antibiotics is by exporting the drug through efflux pumps. Resistance is multi-factorial; however, one promiscuous mechanism covering resistance to diverse antibiotic classes is the expression of the resistance-nodulation-division (RND) superfamily exporters. Efflux pumps actively mediate the transport of small molecules, including antibiotics, from the interior of the bacteria (cytosol), across the inner membrane (IM), periplasm and outer membrane (OM), and into the extracellular environment. RND efflux pumps are present in all Gram-negative pathogens and in addition to playing a central role in the inherent antibiotic resistance, they also pay important roles biofilm formation, persister cells, virulence, and the emergence of resistance mutations in the multidrug resistance (MDR) of Gram-negative pathogens.
The E. coli AcrAB-TolC system is the best studied family member of the RND efflux pumps. Efflux Pump Inhibitor compounds (EPIs) that target the AcrAB-TolC efflux pump inhibit not only bacteria residing within host cells but also persister calls and biofilm formation, suggesting the potential for efficacy against bacterial pathogens during intra- and extra-cellular states.
SAFIRE Screening Platform
Bactria has exclusively licensed a proprietary, scalable, high-throughput screening platform called SAFIRE (Screen for Anti-infectives using Fluorescence microscopy of IntracellulaR Enterobacteriaceae) developed in the Detweiler laboratory at CU Boulder. SAFIRE is a mammalian-cell based model of Gram-negative infection that inherently counter selects against compounds that are toxic to mammalian cells. Currently, there are no FDA-approved EPIs; previous research aimed at developing EPIs failed due to toxicity and/or poor tolerability. Using SAFIRE a series of potent EPIs have been identified that lack toxicity is the assay and were tolerated in mice when administered as a two-dose schedule at 25mg/kg over two consecutive days. Our leading EPIs lack intrinsic antibacterial activity; however, using clinically relevant MDR Gram-negative bacteria selected EPIs have demonstrated significant antibiotic-potentiating activity across classes of commonly used antibiotics, including tetracyclines, fluoroquinolones, chloramphenicol, and polymyxins. Optimized derivatives of these EPIs may synergize with host cellular immune defenses as well as with existing antibiotics, representing an important new class of therapeutics for the treatment MDR Gram-negative bacterial infections.
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