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

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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.

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Shearer, J. D., Saylor, M. L., Butler, C. M., Treston, A. M., Heine, H. S., Chirakul, S., … Warfield, K. L. (2019). GC-072, a novel therapeutic candidate for oral treatment of melioidosis and infections caused by select biothreat pathogens. Antimicrobial Agents and Chemotherapy, 63(12). https://doi.org/10.1128/AAC.00834-19

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