Uncovering the structures and mechanisms for the largest group of bacterial surface virulence factors

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dc.contributor.authorPaxman, Jen_AU
dc.contributor.authorVo, JLen_AU
dc.contributor.authorMartínez Ortiz, Gen_AU
dc.contributor.authorTotsika, Men_AU
dc.contributor.authorLo, AWen_AU
dc.contributor.authorHor, Len_AU
dc.contributor.authorPanjikar, Sen_AU
dc.contributor.authorSchembri, MAen_AU
dc.contributor.authorHeras, Ben_AU
dc.date.accessioned2024-02-28T04:54:00Zen_AU
dc.date.available2024-02-28T04:54:00Zen_AU
dc.date.issued2021-08-14en_AU
dc.date.statistics2023-04-18en_AU
dc.description.abstractWe know so little about how bacteria utilise surface virulence factors to colonise, infect, persist and cause disease in their hosts. The largest group of these virulence factors are the autotransporters, where although they employ a simple process for translocation to the bacterial surface, their functional passenger domains show a diverse range of pathogenic functions such as promoting adhesion, biofilm formation, invasion and tissue destruction. Despite extensive international efforts at the genotype-phenotype level that have confirmed the association of autotransporters with bacterial pathogenesis, less than 0.6 % of their structures have been determined with very little information on their molecular mechanisms of action. With 10 new structures of autotransporter passenger domains over the past few years our group has been leading this area of research. Taking advantage of many autotransporter passenger domains being based upon large >500 residue β-solenoid structures, we have successfully employed Xenon derivatisation at the Australian Synchrotron to acquire anomalous signal for structure determination by single isomorphous replacement. More importantly, we have used our crystal structures to inform a comprehensive array of biophysical, biochemical and microbiological approaches to uncover the mode of action of the autotransporters and their roles in bacterial pathogenesis. Using this approach, we were the first to determine the molecular mechanism of an autotransporter adhesin1. We found that this Ag43 adhesin from Uropathogenic E. coli (UPEC) promoted bacterial biofilms through a self-association mechanism between neighbouring E. coli cell surfaces. This knowledge on biofilms is critical given their contribution to bacterial chronic infections and the development of antibiotic resistance. Here we present the first crystal structure and mechanism of action of an autotransporter adhesin that binds to host tissue to facilitate bacterial colonisation2. The crystal structure of UpaB from UPEC was found to display significant modifications to its β-helix that creates two different binding sites, allowing it to interact simultaneously with both host surface proteins and polysaccharides. As shown in live animal models, both sites co-operate to achieve bacterial colonisation. In contrast to Ag43 that forms self-associations that lead to biofilms, UpaB through directly binding host factors to facilitate colonisation creates a second mechanistic group of the autotransporter adhesins. Returning to Ag43, we also investigate the conservation of its self-association mechanism with 3 new crystal structures of Ag43 homologues from widespread E. coli pathogens3. We show that adaptations to this mechanism of action alter the kinetics of bacterial aggregation and biofilm formation, presumably to suit the different E. coli pathogens to their specific infection sites. Even more importantly, we are using our molecular knowledge on autotransporters such as Ag43 to develop new classes of anti-bacterial inhibitors. To date we have developed and patented a successful inhibitor that targets Ag43 to prevent pathogenic E. coli biofilms4. Again using X-ray crystallography, we have determined the structure of the first autotransporter adhesin-inhibitor complex to fully understand how this novel inhibitor interacts with Ag43 and blocks its function. © The Authorsen_AU
dc.identifier.citationPaxman, J., Vo, J., Martinez Ortiz, G., Totsika, M., Lo, A., Hor, L., Panjikar, S., Schembri, M., & Heras, B. (2021). Uncovering the structures and mechanisms for the largest group of bacterial surface virulence factors. Paper presented to the IUCr 2021, 25th Congress of the International Union of Crystallography, 14-22 August 2021, Prague, Czech Republic. In Acta Crystallographica Section A : Foundations and Advances, 77(a2), C101-C102. doi:10.1107/S0108767321095787en_AU
dc.identifier.conferenceenddate2021-08-22en_AU
dc.identifier.conferencenameIUCr 2021, 25th Congress of the International Union of Crystallography,en_AU
dc.identifier.conferenceplacePrague, Czech Republicen_AU
dc.identifier.conferencestartdate2021-08-14en_AU
dc.identifier.issn2053-2733en_AU
dc.identifier.issuea2en_AU
dc.identifier.journaltitleActa Crystallographica Section A : Foundations and Advancesen_AU
dc.identifier.otherMS-09-3en_AU
dc.identifier.paginationC101-C102en_AU
dc.identifier.urihttps://doi.org/doi:10.1107/S0108767321095787en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15477en_AU
dc.identifier.volume77en_AU
dc.language.isoenen_AU
dc.publisherInternational Union of Crystallographyen_AU
dc.subjectBacteriaen_AU
dc.subjectSurfacesen_AU
dc.subjectInfectious diseasesen_AU
dc.subjectVirulenceen_AU
dc.subjectTranslocationsen_AU
dc.subjectPathogenesisen_AU
dc.subjectANSTOen_AU
dc.subjectAustralian organizationsen_AU
dc.subjectColiformsen_AU
dc.titleUncovering the structures and mechanisms for the largest group of bacterial surface virulence factorsen_AU
dc.typeConference Abstracten_AU
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