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Title: Drug repurposing screen to identify new therapeutics for the Carbapenem-resistant Klebsiella pneumonia

Wednesday, September 24, 2014 — Poster Session IV

10:00 a.m. –12:00 p.m.

FAES Academic Center

NCATS

MICROBIO-2

* FARE Award Winner

Authors

  • S Dai
  • W Sun
  • R. A. Weingarten
  • P Shinn
  • J. C. McKew
  • K. M. Frank
  • W Zheng

Abstract

Multidrug-resistant bacteria have emerged as a significant worldwide public health problem. It is estimated a minimum of 2 million illnesses and 23, 000 deaths annually caused by antibiotic resistance in the U.S. Some multidrug-resistant bacteria are already the culprits of outbreaks in hospitals, such as Klebsiella pneumonia, which broke out at the NIH Clinical Center at 2011. Klebsiella pneumonia with the ability to produce extended-spectrum beta-lactamases (ESBL) is resistant to many classes of antibiotics. Infections caused by carbapenem-resistant strains have few treatment options and are associated with mortality rates upwards of 50%. Here, we report 28 and 27 potent compounds for two different strains of carbapenem-resistant Klebsiella pneumonia, respectively, by conducting phenotypic screening of 5545 small molecules (from LOPAC and NPC) using 1536-well plate absorbance assay and luminesence cell viability assay. 4 hit compounds, including 3'-Azido-3'-deoxythymidine, auranofin, polymyxin B and demeclocycline, not only exhibited single therapeutic effect, but also showed significant synergistic effect with gentamicin, which is sensitive for both of these two strains. Specifically, when combined with 10 ┬ÁM gentamicin, both 3'-Azido-3'-deoxythymidinen and auranofin were 14-fold more potent than that in monotherapy; demeclocycline was 6.5-fold more potent; and polymyxin B was dramatically 143-fold more potent.

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