Abstract
Burkholderia pseudomallei is the causative agent of melioidosis, a disease that requires long-term treatment regimens with no assurance of bacterial clearance. Clinical isolates are intrinsically resistant to most antibiotics and in recent years, isolates have been collected that display resistance to frontline drugs. With the expanding global burden of B. pseudomallei, there is a need to identify new compounds or improve current treatments to reduce risk of relapse. Using the Pathogen Box generated by Medicines for Malaria Venture, we screened a library of 400 compounds for bacteriostatic or bactericidal activity against B. pseudomallei K96243 and identified seven compounds that exhibited inhibitory effects. New compounds found to have function against B. pseudomallei were auranofin, rifampicin, miltefosine, MMV688179, and MMV688271. An additional two compounds currently used to treat melioidosis, doxycycline and levofloxacin, were also identified in the screen. We determined that the minimal inhibitory concentrations (MIC) for levofloxacin, doxycycline, and MMV688271 were below 12 μg/ml for 5 strains of B. pseudomallei. To assess persister frequency, bacteria were exposed to 100x MIC of each compound. Auranofin, MMV688179, and MMV688271 reduced the bacterial population to an average of 4.53 × 10−6% compared to ceftazidime, which corresponds to 25.1% survival. Overall, our data demonstrates that auranofin, MMV688197, and MMV688271 have the potential to become repurposed drugs for treating melioidosis infections and the first evidence that alternative therapeutics can reduce B. pseudomallei persistence.
Highlights
Burkholderia pseudomallei is the causative agent of melioidosis, a disease originally of importance in Southeast Asia and Northern Australia (Currie et al, 2000; Sarovich et al, 2012a,b; Hatcher et al, 2015)
B. pseudomallei can be introduced into previously non-endemic areas and persist in the environment (Limmathurotsakul et al, 2016)
In addition to Asia and Australia, the endemic presence of the pathogen has been confirmed in South America and the Caribbean
Summary
Burkholderia pseudomallei is the causative agent of melioidosis, a disease originally of importance in Southeast Asia and Northern Australia (Currie et al, 2000; Sarovich et al, 2012a,b; Hatcher et al, 2015). Depending on the clinical manifestations of the disease, treatment for B. pseudomallei is usually biphasic, starting with 10–14 days of intravenous therapy, followed by. The most commonly administered intravenous drugs consist of ceftazidime with or without trimethoprim-sulfamethoxazole (TMP-SMX), amoxicillin–clavulanic acid, imipenem, and cefoperazone/sulbactam (Estes et al, 2010). The second phase of treatment consists of a minimum of 3 months of oral chloramphenicol, TMP-SMX, and doxycycline, or amoxicillin-clavulanic acid (Estes et al, 2010)
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