Despite these differences, the genes shared by the two isolates have an average identity of 99% at the nucleotide level [19, 26]. The genomic sequence of LB-100 in vivo several B. pseudomallei and B. mallei isolates are also publicly available through the NCBI genomic BLAST service (http://​www.​ncbi.​nlm.​nih.​gov/​sutils/​genom_​table.​cgi),

which provides a wealth of resources to study these organisms. B. pseudomallei causes the human disease melioidosis, which is notoriously difficult to diagnose. Clinical manifestations vary greatly and may present as flu-like symptoms, benign pneumonitis, acute and chronic pneumonia, or fulminating septicemia. Infection occurs via inhalation of Alisertib in vivo contaminated aerosol particles or through skin abrasions, and the risk of contracting the disease is proportional to the concentration of B. pseudomallei in soil and water. In endemic areas, heavy rainfalls result in a shift from percutaneous inoculation to inhalation as the primary mode of infection, which leads to a more severe illness. Melioidosis commonly BYL719 order affects the lungs and is characterized by the spread of bacteria to various internal organs including the spleen and liver. Many patients become bacteremic and

the mortality rate is high (19-51%) despite aggressive antimicrobial therapy [1–9]. B. pseudomallei is refractory to most antibiotics and resistance mechanisms include efflux pumps and β-lactamases [27–36]. The recommended treatment entails the use of ceftazidime, carbapenems, TMP-SMZ, chloramphenicol and/or Augmentin for several weeks. Response to Clomifene treatment is slow and eradication of B. pseudomallei is difficult to achieve, resulting in recrudescence [1, 37–39]. B. mallei causes the zoonosis glanders, which primarily affects solipeds [8, 9, 20–25]. In humans, infection occurs by contact with infected animals via the cutaneous or respiratory route. The clinical manifestations of the disease include febrile pneumonia associated with necrosis of the tracheobronchial tree or pustular skin lesions and the development of abscesses.

Most patients become bacteremic and B. mallei disseminates to the liver and spleen where it rapidly causes necrosis. Even with antibiotic treatment, the mortality rate for human glanders is 50% and the basis for this high mortality rate is not understood, though B. mallei has been shown to be resistant to complement-mediated killing [40], macrophages [41] and antimicrobials [32, 42]. One key aspect of pathogenesis by B. mallei and B. pseudomallei is their ability to invade and multiply within a variety of eukaryotic cells, where bacteria are shielded from the host humoral immune response and antibiotics. Once internalized, B. mallei and B. pseudomallei escape from endocytic vacuoles and enter the cytoplasm of infected cells where they multiply. The organisms subsequently spread to neighboring cells through a process involving the formation of actin tails and membrane protrusions that push bacteria from one cell to another.