Thinking Outside the Bug: Targeting Outer Membrane Proteins for Burkholderia Vaccines

Abstract

Increasing antimicrobial resistance due to misuse and overuse of antimicrobials, as well as a lack of new and innovative antibiotics in development has become an alarming global threat. Preventative therapeutics, like vaccines, are combative measures that aim to stop infections at the source, thereby decreasing the overall use of antibiotics. Infections due to Gram-negative pathogens pose a significant treatment challenge because of substantial multidrug resistance that is acquired and spread throughout the bacterial population. Burkholderia spp. are Gram-negative intrinsically resistant bacteria that are responsible for environmental and nosocomial infections. The Burkholderia cepacia complex are respiratory pathogens that primarily infect immunocompromised and cystic fibrosis patients, and are acquired through contaminated products and equipment, or via patient-to-patient transmission. The Burkholderia pseudomallei complex causes percutaneous wound, cardiovascular, and respiratory infections. Transmission occurs through direct exposure to contaminated water, water-vapors, or soil, leading to the human disease melioidosis, or the equine disease glanders. Currently there is no licensed vaccine against any Burkholderia pathogen. This review will discuss Burkholderia vaccine candidates derived from outer membrane proteins, OmpA, OmpW, Omp85, and Bucl8, encompassing their structures, conservation, and vaccine formulation.

Predictive and Experimental Immunogenicity of Burkholderia Collagen-like Protein 8-Derived Antigens

“…As reported previously [20], the two surface-exposed loops of Bucl8 are well conserved within the Burkholderia clade of animal pathogens, including the majority species from the Burkholderia cepacia complex (BCC), Burkholderia mallei, Burkholderia thailandensis (although generally non-infectious), and Burkholderia pseudomallei. Thus, the β-barrel loops could be a viable vaccine target for all these species.…”

“…BepiPred is based on a random forest algorithm trained on epitopes annotated from antibody-antigen protein structures. Structure based epitope prediction was performed using ElliPro [25] and Discotope [26], starting from the homology model of Bucl8 (residues 84-505) [20]. Discotope identifies discontinuous B cell epitopes, i.e., epitopes whose residues are distantly placed in the sequence albeit close in space in the three-dimensional structure of the protein antigen.…”

“…Vaccines were formulated with antigens derived from Bucl8 that were predicted to be extracellular in homology models [20]. Two main antigen types were tested: (i) recombinant proteins rBucl8-CL-Ct and rBucl8-Ct and (ii) synthetic peptide-conjugates pepL1 and pepL2.…”

“…We have recently homology modelled the structure of the B. pseudomallei outermembrane protein Bucl8 and identified extracellular components as potential vaccine targets [20]. Here, we employed a number of bioinformatic tools to predict immunogenic epitopes, then, tested those antigens experimentally.…”

“…A prior study determined the recombinant protein, produced in Escherichia coli, corresponding to Bucl8's CL-Ct component forms a collagen triple helix [19]. Additionally, homology modelling has predicted two main surface-exposed structures that have the potential to be targeted for a subunit vaccine: the β-barrel-loops L1 and L2, and the extended extracellular CL-Ct portion [20].…”