Introduction: Melioidosis is a significant health problem within endemic areas such as Southeast Asia and Northern Australia. The varied presentation of melioidosis and the intrinsic antibiotic resistance of Burkholderia pseudomallei, the causative organism, make melioidosis a difficult infection to manage. Often prolonged courses of antibiotic treatments are required with no guarantee of clinical success. Areas covered: B. pseudomallei is able to enter phagocytic cells, affect immune function, and replicate, via manipulation of the caspase system. An examination of this mechanism, and a look at other factors in the pathogenesis of melioidosis, shows that there are multiple potential points of therapeutic intervention, some of which may be complementary. These include the directed use of antimicrobial compounds, blocking virulence mechanisms, balancing or modulating cytokine responses, and ameliorating sepsis. Expert commentary: There may be therapeutic options derived from drugs in clinical use for unrelated conditions that may have benefit in melioidosis. Key compounds of interest primarily affect the disequilibrium of the cytokine response, and further preclinical work is needed to explore the utility of this approach and encourage the clinical research needed to bring these into beneficial use.

Melioidosis caused by the facultative intracellular pathogen Burkholderia pseudomallei is difficult to treat due to poor intracellular bioavailability of antibiotics and antibiotic resistance. In the absence of novel compounds, polymersome (PM) encapsulation may increase the efficacy of existing antibiotics and reduce antibiotic resistance by promoting targeted, infection-specific intracellular uptake. In this study, we developed PMs composed of widely available poly(ethylene oxide)-polycaprolactone block copolymers and demonstrated their delivery to intracellular B. thailandensis infection using multispectral imaging flow cytometry (IFC) and coherent anti-Stokes Raman scattering microscopy. Antibiotics were tightly sequestered in PMs and did not inhibit the growth of free-living B. thailandensis. However, on uptake of antibiotic-loaded PMs by infected macrophages, IFC demonstrated PM colocalization with intracellular B. thailandensis and a significant inhibition of their growth. We conclude that PMs are a viable approach for the targeted antibiotic treatment of persistent intracellular Burkholderia infection.

Melioidosis is a neglected tropical disease caused by the bacterium Burkholderia pseudomallei . The bacterium is intrinsically resistant to various antibiotics and melioidosis is therefore difficult to treat successfully without relapse in infection. B. pseudomallei is an intracellular pathogen, and therefore to eradicate the infection, antimicrobials must be able to access bacteria in an intracellular niche. This study assessed the ability of a panel of monoclonal antibodies to opsonise Burkholderia species and determine the effect that the antibody has on bacterial virulence in vitro . Murine macrophage infection assays demonstrated that monoclonal antibodies to the capsule of B. pseudomallei are opsonising. Furthermore, one of these monoclonal antibodies reduced bacterial actin tail formation in our in vitro assays, indicating antibodies could reduce the intracellular spread of B. thailandensis . The data presented in this paper demonstrates that monoclonal antibodies are opsonising and can decrease bacterial actin tail formation, thus decreasing their intracellular spread. This data has informed selection of an antibody for development of an antibody-antibiotic conjugate for melioidosis. Importance statement Melioidosis is difficult to treat successfully due to the bacterium being resistant to many classes of antibiotics, therefore available therapeutic options are limited. New and improved therapies are urgently required to treat this disease. Here we have investigated the potential of monoclonal antibodies to target this intracellular pathogen. We have demonstrated that monoclonal antibodies can target the bacterium, increase uptake into macrophages and reduce actin tail formation required by the bacterium for spread between cells. Through targeting the bacterium with antibodies we hope to disarm the pathogen, reducing the spread of infection. Ultimately we aim to use an opsonising antibody to deliver antibiotics intracellularly by developing an antibody-antibiotic conjugate therapeutic for melioidosis.

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