In spite of the high level of global childhood immunization, whooping cough, caused by the Gram-negative bacterial pathogen Bordetella pertussis, causes an estimated 20-40 million infections every year and remains the fifth-leading cause of vaccine-preventable death in children under 5 years of age. Reported pertussis infections in countries with a high vaccination coverage are on the increase across all age groups, emphasizing the need for reinforcing existing vaccination strategies and finding new preventative drugs to target this highly contagious and acute respiratory illness.

The 130 kDa autotransporter (AT) Bordetella serum-resistance killing protein A (BrkA) is an important virulence factor that confers serum resistance, and is a promising candidate antigen for improving existing acellular pertussis vaccines in humans. It consists of a short N-terminal signal peptide, a functional Passenger Domain (PD) and a C-terminal β-domain which ensures that the PD is translocated across the bacterial outer membrane. In a recent paper published in the Biochemical Journal (http://www.biochemj.org/bj/ev/435/0577/bj4350577_ev.htm), Prof. Fei Sun and colleagues from the National Laboratory of Biomacromolecules, in collaboration with Neil Isaacs from the University of Glasgow, UK, solve the crystal structure of the BrkA b–domain at a 3 angstrom resolution, and provide structural insights into how the PD is translocated across the outer membrane. Using structural analysis and mutagenesis studies, Prof. Sun’s group reveal that there is a hydrophobic cavity at the extracellular entrance of the b–domain which is crucial for PD translocation. This new understanding of how this virulence factor is assembled and secreted, and of which elements of the b–domain are important for PD translocation, will facilitate drug development as this domain is a potential target for the design of compounds that inhibit translocation of virulence factors across the outer membrane.

This study was recently selected as a “Key Scientific Article” by Global Medical Discovery, a Canadian pharmaceutical information company (http://globalmedicaldiscovery.com/) which provides the latest biomedical information for the pharmaceutical industry and academic institutions.

Fig. Extracellular hydrophobic cavities of AT β-domains. The electrostatic potential surface of the extracellular hydrophobic cavity in BrkAβ(A). (B)The labeled hydrophobic residues forming the cavity are shown as white sticks and the basic residues on L4 as slate sticks (B). Strands S2, S3, S5 and S6, and loop L4 are labeled accordingly. For comparison, electrostatic potential surfaces of Nalpβ (C), EspPβ (D) and EstAβ (E) are shown in the same orientation as BrkAβ. The electrostatic potential was calculated using DelPhi and all panels were produced using PyMol (http://www.pymol.org).