GC-072, a novel therapeutic candidate for oral treatment of melioidosis and infections caused by select biothreat pathogens

Jeffry D. Shearer, Michelle L. Saylor, Christine M. Butler, Anthony M. Treston, Henry S. Heine, Sunisa Chirakul, Herbert P. Schweizer, Arnold Louie, George L. Drusano, Steven D. Zumbrun, Kelly L. Warfield

Research output: Contribution to journalArticlepeer-review

Abstract

Burkholderia pseudomallei, the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from B. pseudomallei varies depending on the type of infection and extent of available health care; in the case of septicemia, left untreated, it can range from 50% to 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for 2 weeks or longer, followed by oral eradication-phase treatment lasting several months. An effective oral therapeutic for outpatient treatment of acute-phase melioidosis is needed. GC-072 is a potent, 4-oxoquinolizine antibiotic with selective inhibitory activity against bacterial topoisomerases. GC-072 has demonstrated in vitro potency against susceptible and drug-resistant strains of B. pseudomallei and is also active against Burkholderia mallei, Bacillus anthracis, Yersinia pestis, and Francisella tularensis. GC-072 is bactericidal both extra- and intracellularly, with rapid killing noted within a few hours and reduced development of resistance compared to that for ceftazidime. GC-072, delivered intragastrically to mimic oral administration, promoted dose-dependent survival in mice using lethal inhalational models of B. pseudomallei infection following exposure to a 24- or 339-LD50 (50% lethal dose) challenge with B. pseudomallei strain 1026b. Overall, GC-072 appears to be a strong candidate for first-line oral treatment of melioidosis.

Original languageEnglish (US)
Article numbere00834-19
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number12
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Antibiotic
  • Biodefense
  • Burkholderia
  • GC-072
  • Melioidosis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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