Discovery of novel anti-infectives for gram negative pathogens

Abstract

Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Tier-1 select pathogens that cause highly lethal human infections with limited therapeutic options. Intercellular spread is a hallmark of Burkholderia pathogenesis and its prominent ties to virulence make it an attractive therapeutic target. We developed a high-throughput cell-based phenotypic assay and screened ˜220,000 small molecules for their ability to disrupt intercellular spread by Burkholderia thailandensis, a BSL-2 surrogate for these pathogens. 268 hits were identified, and cross-species validation found 32 hits that also disrupt intercellular spread by Bp and/or Bm. In a fulminant murine model of respiratory melioidosis, treatment with a number of these agents was significantly more effective than ceftazidime, the current drug of choice, for improving patient survival and decreasing bacterial counts in major organs.

Dependencies are inferred from the claim text.