My lab has been engaged in melioidosis research since 2001. When I first started working on the causative agent Burkholderia pseudomallei, it was a relatively obscure bacterium endemic in Southeast Asia and Northern Australia. This changed after the 911 terrorist attacks. B. pseudomallei is classified as a potential bioterrorism agent and on the USA select agent list. In Singapore, work with the agent requires containment in BSL3 labs and the “Protected Place” status.

 

Over the years, we have learned much about this enigmatic and versatile bacterium with an extremely broad host range. It lurks in the soil, and is an accidental human pathogen where humans are dead end hosts. We and others discovered that the organism employs two secretion systems, known as the Type 3 and Type 6 Secretion Systems, to escape the endosome into the cytosol and fuse neighboring cells together respectively. We identified a signaling cascade that coordinates the turning on of these two secretion systems one after the other that is critical for bacteria to cause disease in the mammalian hosts. We also discovered the immune responses elicited by the infection, and how a low ratio of reduced glutathione to oxidized glutathione (reflection of oxidative stress) affects the host’s immune response to the bacteria and is one of the factors that explains why Type 2 diabetic patients are so much more susceptible to melioidosis.  For more information on melioidosis and to connect with the melioidosis research and clinical community at the International Melioidosis Network, go to the website.

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I also initiated research on hypervirulent Klebsiella pneumoniae since 2015 on Klebsiella induced liver abscess because of the high incidence in parts of Asia, including Singapore. We have found a different pattern of infection in different ethnic groups in Singapore, where certain lineages of hypervirulent K. pneumoniae are associated predominantly in the Chinese population. Our ongoing studies examine the role of hypermucoid capsule of the K1 lineage, the iron siderophores, colibactin and microcin loci in the bacteria in contributing to different stages of the disease. We have now expanded our studies to examine the transmission of antibiotic resistance in carbapenem-resistant K. pneumoniae due to the urgent threat of rising antibiotic resistance worldwide. The World Health Organization (WHO) lists Carbapenem-resistant Enterobacterales (CRE) under Critical Priority 1 in the Global Priority of Antibiotic Resistant Bacteria document in 2017. We believe that many of the successful and dominant clinical plasmids carrying drug-resistance in hospital patients reflect adaptations and novel properties of these mobile genetic elements and unique adaptations in their preferred hosts.  Our goal is to define what these properties and interactions are and how we could harness this knowledge to design strategies to slow down or ameliorate transmission.