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The Tripartite Tricarboxylate Transporter (TTT) family: investigating signalling and transport networks in the re-emerging pathogen Bordetella pertussis

Abstract

Pertussis, or whooping cough, is a pulmonary-tract disease caused by the Gram-negative bacterium Bordetella pertussis. Affecting mainly children under four years old, this disease is characterized by persistent cycles of cough which can lead to pulmonary tissue damage and necrosis. Despite the existing vaccine, several new pertussis epidemies have been described over the last years, elevating the status of B. pertussis to re-emerging pathogen. Encoded on the genome of species from the Bordetella genus, a family of high affinity uptake systems, the Tripartite Tricarboxylate Transporters (TTT) is found to be highly overrepresented. The TTT family is composed by a 12-15 transmembrane translocator domain TctA, a four transmembrane domain with unknown function TctB and a periplasmic Substrate Binding Protein (SBP) TctC. B. pertussis have 78 genes encoding for TctC proteins, making it the most abundant gene family in the genome, in contrast to only 2 TctAB systems. Widespread in the bacterial kingdom, the TTT family is particularly abundant in alpha and beta-proteobacteria. However, B. pertussis is the only strict pathogen to show a similar expansion. Despite initial indications pointing to an involvement of the TTT SBPs in virulence and core metabolism, the role of this protein family in B. pertussis remains elusive. Moreover, the ligand translocation mechanism of the TTT family remains unknown. This study aims to (i) determine the translocation mechanism of the TTT family studying the citrate transport system TctCBA as a prototype, using CryoEM, (ii) investigate the involvement of the TctC homologs in the core metabolism and pathogenicity of this reemeging pathogen and (iii) design a molecular inhibitor of the TctC homologs in order to collapse B. pertussis metabolism. Together, these results will deepen our understanding of B. pertussis metabolism and pathogenesis process, leading to potential novel drug targets for the treatment of whooping cough, as well as elucidate the transport mechanism of a family of transporters ubiquitously found among bacteria. (AU)

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