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Team on stage: Laura Cendron’s group

The team: : PI: Laura Cendron; PhD students: Sofia De Felice, Monica Chinellato; Postdoc: Filippo Vascon; Graduate fellow: Angela Pavan; Marie-Curie Fellow (co-hosting Institution): Antonella Pasquato.

Contacts:  http://www.bio.unipd.it/synbio/

Description: Our Structural Biology Research Unit, at the Dept of Biology, University of Padua (Italy) is focusing its efforts on two main research lines: the discovery of novel strategies to contrast antimicrobial resistance and the development of novel diagnostic and therapeutic tools based on albumin and nanobodies.

Modern medicine relies on the availability of effective antibiotics. Not only infectious diseases but also surgical interventions, chronic diseases and cancer treatments can be tackled only if our antimicrobials arsenal is efficient. After half a century of successful control of bacterial infections, the spread of Multi-Drugs Resistant Bacteria is becoming a global emergency.

We have been involved for long time in the design and optimization of lead compounds against  b-lactamase enzymes. Collaborating with an international network of chemists, computational biologists and microbiologists, we constantly investigate by X-ray crystallography the binding determinants of b-lactamase inhibitors, thus shedding light on their mechanism of action and fostering the design of improved drugs.

Recently, we have explored a novel approach to contrast resistance acquisition by bacterial pathogens, in line with  the paradigm of “anti-evolution” drugs. Indeed, we discovered nanobodies able to inhibit the widely conserved SOS response in bacteria. Such pathway, activated in reply to genotoxic stress, is recognized as one of the main drivers of acquisition of antimicrobial resistance. By targeting the LexA repressor-protease, whose activity controls SOS genes, we blocked their expression in bacterial cultures models. Structural description of the novel LexA-nanobody complexes reveal they function by stabilizing LexA in its inactive conformation and preventing co-proteolysis by Recombinase A. Our research in this context is now moving toward: 1) the optimization of nanobodies as deliverable inhibitors; 2) the characterization of SOS response machinery in P. aeruginosa by integrated techniques; 3) the translation of the obtained results in P. aeruginosa.

Recent achievements:

Maso L, Vascon F, Chinellato M, Goormaghtigh F, Bellio P, Campagnaro E, Van Melderen L, Ruzzene M, Pardon E, Angelini A, Celenza G, Steyaert J, Tondi D, Cendron L. Nanobodies targeting LexA autocleavage disclose a novel suppression strategy of SOS-response pathway. Structure. 2022 Nov 3;30(11):1479-1493. https://doi: 10.1016/j.str.2022.09.004.

Legru A., Verdirosa F., Vo-Hoang Y., Tassone G., Vascon F., Thomas C. A., Sannio F., Corsica G., Benvenuti M., Feller G., Coulon R., Marcoccia F., Devente S. R., Bouajila E., Piveteau C., Leroux F., Deprez-Poulain R., Deprez B., Licznar-Fajardo P., Crowder M.W., Cendron L., Pozzi C., Mangani S., Docquier J.D., Hernandez J.F. Gavara. Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates. Journal of Medicinal Chemistry. 2022; 65(22), 15457–15472. https://doi.org/10.1021/acs.jmedchem.2c01257