Abstract
The tropical pathogen Burkholderia pseudomallei requires long-term parenteral antimicrobial treatment to eradicate the pathogen from an infected patient. However, the development of antibiotic resistance is emerging as a threat to this form of treatment. To meet the need for alternative therapeutics, we proposed a screen of natural products for compounds that do not kill the pathogen, but in turn, abrogate bacterial virulence. We suggest that the use of molecules or compounds that are non-bactericidal (bacteriostatic) will reduce or abolish the development of resistance by the pathogen. In this study, we adopted the established Caenorhabditis elegans-B. pseudomallei infection model to screen a collection of natural products for any that are able to extend the survival of B. pseudomallei infected worms. Of the 42 natural products screened, only curcumin significantly improved worm survival following infection whilst not affecting bacterial growth. This suggested that curcumin promoted B. pseudomallei-infected worm survival independent of pathogen killing. To validate that the protective effect of curcumin was directed toward the pathogen, bacteria were treated with curcumin prior to infection. Worms fed with curcumin-treated bacteria survived with a significantly extended mean-time-to-death (p < 0.0001) compared to the untreated control. In in vitro assays, curcumin reduced the activity of known virulence factors (lipase and protease) and biofilm formation. To determine if other bacterial genes were also regulated in the presence of curcumin, a genome-wide transcriptome analysis was performed on curcumin-treated pathogen. A number of genes involved in iron acquisition and transport as well as genes encoding hypothetical proteins were induced in the presence of curcumin. Thus, we propose that curcumin may attenuate B. pseudomallei by modulating the expression of a number of bacterial proteins including lipase and protease as well as biofilm formation whilst concomitantly regulating iron transport and other proteins of unknown function.
Highlights
Burkholderia pseudomallei is the causative agent of the tropical disease, melioidosis, which is endemic in Southeast Asia and northern Australia (Wiersinga et al, 2006)
Bacterial Isolates and Nematode Strains B. pseudomallei clinical isolates R15 (Lee et al, 2007), K96243 (Holden et al, 2004) and UM6 as well as Enterococcus faecalis V583 were grown in BHI broth, Pseudomonas aeruginosa strain PA14 in King’s B broth, Staphylococcus aureus strain NCTC83254 and methicillin-resistant S. aureus (MRSA) strain ATCC33591 in Trypticase Soy (TS) media while Escherichia coli strain OP50 and Salmonella typhimurium SL1344 were cultured in Luria Bertani (LB) broth
We extended the utility of the B. pseudomallei - C. elegans infection model to screen for anti-infectives that rescue the worm from infection
Summary
Burkholderia pseudomallei is the causative agent of the tropical disease, melioidosis, which is endemic in Southeast Asia and northern Australia (Wiersinga et al, 2006). Melioidosis accounts for the high overall mortality in northeast Thailand and is reported to be the third leading cause of Curcumin attenuates B. pseudomallei death from infectious diseases after human immunodeficiency virus (HIV)-AIDS and tuberculosis (Limmathurosatkul et al, 2010). Treatment of melioidosis is still solely dependent on a lengthy course of antibiotics. B. pseudomallei is becoming increasingly resistant to a diverse group of antimicrobials including third generation cephalosporins whilst quinolones and aminoglycosides have no reliable effect (Puthucheary and Sam, 2012). Two important antibiotic candidates in melioidosis treatment are ceftazidime and amoxicillin-clavulanic acid and cases of resistance have been reported in recent years (Wuthiekanun et al, 2011). There is an urgent need for new alternative treatments for this disease
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