Our Research
Healthcare-Associated Infections (HAIs) occur while a patient is attending healthcare facility and/or receiving care a primary condition. HAIs are a major problem in U.S. hospitals with 1.3 million HAIs reported annually and almost 100,000 HAI-related deaths. Over 500,000 of these HAIs are caused by Gram-negative bacteria, many of which are resistant to multiple
antibiotics. Annually, Gram negative HAIs in the U.S. cause >32,000 deaths and an estimated $14 billion in excess inpatient costs. Consequently, HAIs caused by Gram-negative bacteria are 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 pivotal role in antibiotic resistance, they also involved in biofilm formation, persister cells, virulence, and the emergence of resistance mutations in multidrug resistant (MDR) 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 infection 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 and cell membranes. Currently, there are no FDA-approved EPIs; key prior research aimed at
developing EPIs failed due to membrane permeabilization and/or mammalian cell toxicity. However, SAFIRE intrinsically eliminates compounds that permeabilize membranes and/or are toxic to mammalian cells.. Using SAFIRE a series of potent EPIs have been identified that lack toxicity in this assay and were tolerated in mice when administered as a two-dose schedule at 25mg/kg over two consecutive days. In non-infection states, 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, cephalosporins, chloramphenicol, and polymyxins. These data support a mechanism of action where our EPIs increase the effective concentration of structurally distinct antibiotics by directly inhibiting bacterial efflux pumps.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.
