Advancement to IND of novel BLI for pairing with cefixime

Project Summary Abstractlactam antibiotics are the most widely used antibiotic class in the U Saccounting for more thanof antibacterial prescriptionsAmong other rolesthey are critical therapeutics for difficult to treat infections due to gram negative pathogens such as EcoliKlebsiella pneumoniaeand Enterobacter sppHoweverthe utility of this class of antibiotics is being rapidly compromised by the alarming spread of newlactamase resistance mechanismsenzymes produced by bacteria that hydrolytically inactivatelactam antibioticsA particularly important concern is the lack of orally bioavailablelactamlactamase inhibitorBLIcombinations capable of addressing this emerging challengeboth in the Biodefense arena and in the hospital community settingsOrally availablelactam combinations with legacy BLIse gamoxicillin clavulanic acid or Augmentindemonstrate reasonable activity against Gram negative pathogens expressing Ambler Class A Extended Spectrum Beta LactamasesESBLsbut lack activity against organisms expressing Class A carbapenemasesKPC typeClass C cephalosporinaseschromosomal and plasmidicand Class D oxacillinasesWe have identified a compound series with potent and broad spectrum activity against these serinelactamasesThese compounds rescue the activity of the orally bioavailable cephalosporin cefixime in MDR strains of Gram negative Enterobacteriaceaeincluding Ecoliand KpneumoniaeMoreoverwe have shown that prototype prodrugs in the series demonstrate striking oral bioavailability in rodentsand that they rescue cefixime activity in murine models of bacterial diseaseThe objectives of this project are to advance the selected Development Candidate to IND filing for use in combination with cefixime Project narrative This application focuses on development of the first oral product able to address the alarming emergence oflactamase expressinghighly resistant NIAID Category C pathogensThe product will be composed of a novelbroad spectrumorally bioavailablelactamase inhibitor plus a known orally bioavailable cephalosporin