Maria Rosalia Pasca
Maria Rosalia Pasca
e-mail:
affiliation: Università di Pavia
research area(s): Genetics And Genomics
Course: Genetics, Molecular and Cellular Biology
University/Istitution: Università di Pavia
ACADEMIC POSITION
From 10/2006: Researcher in Microbiology (BIO/19) (confirmed from 10/2009), Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia.

EDUCATION
· 21/03/1997: Degree in Natural Sciences (110/110), University of Bari.
· 04/02/2002: PhD in Genetics and Molecular Evolution, University of Bari.

PROFESSIONAL EXPERIENCES
· 1998-2002: PhD student in the Laboratory of Genetics of Microorganisms, University of Bari (supervisor: Prof. M.S. Ciampi).
· 12/1998-01/1999: Stages in the Laboratory of Molecular Genetics, University of Camerino (supervisor: Prof. C. Gualerzi).
· 1999, 2001: Stages in the Laboratory of Molecular Genetics, University of Ancona (supervisor: Prof. A. La Teana).
· 01-12/2000: Stage in the Laboratory of Molecular Genetics of CNRS de Gif-sur-Yvette, Paris, France (supervisor: Dr. L. Bossi).
· 04/2002-09/2006: Post-Doc in the Laboratory of Molecular Microbiology, University of Pavia (supervisor: Prof. G. Riccardi).

DIDACTICS
Official teachings
· 2007-2008: In the "SILSIS Speciality School" (University of Pavia), Professor of the following courses: Didactics of Microbiology (20 h) and Didactics of Microbiology (15 h) and Food Microbiology Laboratories (15 h) for 13A, 57A, 60A classes, University of Pavia.
· 2008-2012: Professor of the course "Pathogen Identifications" (3 CFU), Master degree in Experimental and Applied Biology (Bioanalysis course), University of Pavia.
· 2009-2010: Professor of the course “Microbiological techniques” (6 CFU), Degree in Biological Sciences (Industrial course), University of Pavia.
· 2009-2010: Professor of the course “Microbiological techniques” (20 h), Speciality School in Microbiology and Virology, University of Pavia.
· 2010-11: Professor of the course “Laboratory of cellular Methodologies (1 CFU), Degree in Biological Sciences (Biomolecular course), University of Pavia.
· From 2010-11: Professor of the course “Environmental Microbiology” (3 CFU), Master degree in Experimental and Applied Biology (Environmental biology and Biodiversity course), University of Pavia.
· From 2012-13: Professor of the course “Microbiological analysis” (3 CFU), Master degree in Experimental and Applied Biology (Bioanalysis course), University of Pavia.
· From 2013-2014: Professor of the course “Laboratory of Experimental Biology” (3 CFU) in Degree in Biotechnology, University of Pavia.
· From 2008: member staff of PhD School in Genetics, Molecular and Cellular biology, University of Pavia (Coordinator: Prof. Antonio Torroni).
Identification of targets for new antitubercular drugs (EC-VII Framework program).
Tuberculosis remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. Moreover, M. tuberculosis strains resistant to several drugs (MDR-TB and XDR-TB) are becoming a threat to public health worldwide. Consequently, there is an urgent necessity of new antitubercular drugs. This research is part of the project "More Medicines for Tuberculosis" (EC-VII, 2011-2015). We have identified the target of the benzothiazinones (BTZ) (EC-VI, 2006-2010) very effective drugs against M. tuberculosis, that is DprE1, an enzyme involved in the biosynthesis of arabinogalactan, a cell wall component.
The study of mechanism of action and resistance of new 19 antitubercular drugs is in progress. For some of these we identified the mechanism of resistance and of action; moreover we are characterizing new targets. Surprisingly new DprE1 inhibitors have been also identified.
In collaboration with Sentinel Diagnostics, we are developing a new diagnostic kit for screening of mycobacterial infections.

A very promising drug against Burkholderia cenocepacia (Fibrosi Cistica 2012).
Burkholderia cenocepacia is considered one of the most serious cystic fibrosis (CF) pathogens and it causes infections in about 3.5% of CF patients worldwide. B. cenocepacia is highly resistant to antibiotics, thus prompting the need for new strategies for the control of infections.
In this project we will pursue three aims:
1. Heterologous production of RND-4 transporter for future structural studies and drug design in order to find molecules that will block this pump.
2. Synthesis of new compounds against B. cenocepacia. We recently found that a pyridine compound is very active and we identified a mechanism of resistance, which relies on the extrusion of the new drug by RND-4 transporter. We aim to synthetize new derivatives that will not be recognized by the pump as a substrate.
3. Target identification of pyridine derivatives through selection and genome sequencing of spontaneous resistant mutants.
CF patients often die because of B. cenocepacia infections. By discovering new drugs against this pathogen, we will be able to improve the treatment of lethal infections due to B. cenocepacia.
1. Federici F, et al. 2004. Characterization and heterologous expression of the oxalyl-CoA decarboxylase gene from Bifidobacterium lactis. Appl Environ Microbiol 70: 5066-73
2. Pasca MR, et al. 2004. Rv2786c-2687c-2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. AAC 48: 3175-8
3. Bellinzoni M, et al. 2005. Glutamine amidotransferase activity of NAD+ synthetase from Mycobacterium tuberculosis depends on an amino-terminal nitrilase domain. Res Microbiol 156: 173-7
4. Pasca MR, et al. 2005. The mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. AAC 49: 4775-7
5. Guglierame P, et al. 2006. Efflux pump genes of the resistance-nodulation-division family in Burkholderia cenocepacia genome. BMC Microbiol 6:66
6. Buroni S, et al. 2006. LfrR is a repressor that regulates expression of the efflux pump LfrA in Mycobacterium smegmatis. AAC 50:4044-52
7. Maciag A, et al. 2007. Global analysis of Mycobacterium tuberculosis FurB regulon. J Bacteriol 189:730-40
8. Riccardi G, et al. 2008. Genomic analysis of zinc homeostasis in Mycobacterium tuberculosis. FEMS Microbiol Lett 287:1-7
9. Milano A, et al. 2009. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpL5-MmpS5 efflux system. Tuberculosis (Edinb) 89:84-90
10. Makarov V, et al. 2009. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324:801-4
11. Riccardi G, et al. 2009. Mycobacterium tuberculosis: drug resistance and future perspectives. Future Microbiol 4:597-614
12. Dalla Valle C, et al. 2009. Control of MRSA infection and colonisation in an intensive care unit by GeneOhm MRSA assay and culture methods. BMC Infect Dis 9:137
13. Buroni S, et al. 2009. Assessment of three Resistance-Nodulation-Cell Division drug efflux transporters of Burkholderia cenocepacia in intrinsic antibiotic resistance. BMC Microbiol 9:200
14. Pasca MR, et al. 2010. Clinical isolates of Mycobacterium tuberculosis in four european hospitals are uniformly susceptible to benzothiazinones. AAC 54:1616-8
15. Perrin E, et al. 2010. Exploring the HME and HAE1 efflux systems in the genus Burkholderia. BMC Evol Biol 10:164
16. Manina G, et al. 2010. Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and role in benzothiazinone resistance. Mol Microbiol 77:1172-85
17. Manina G, et al. 2010. Decaprenylphosphoryl-β-D-ribose 2’-epimerase from Mycobacterium tuberculosis is a magic drug target. Current med chem 17:3099-108
18. Lucarelli AP, et al. 2010. Mycobacterium tuberculosis phosphoribosyl pyrophosphate synthetase: biochemical features of a crucial enzyme for mycobacterial cell wall biosynthesis. PloS One 5:e15494
19. Bazzini S, et al. 2011. Deciphering the role of RND efflux transporters in Burkholderia cenocepacia. PLoS One 6:e1902
20. Menendez C, et al. 2011. Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents. Eur J Med Chem 46:5524-31
21. Ribeiro AL, et al. 2011. Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. PLoS One 6:e26675
22. Pasca MR, et al. 2012. Evaluation of fluoroquinolone resistance mechanisms in Pseudomonas aeruginosa MDR clinical isolates. Microb Drug Resist 18:23-32
23. La Rosa V, et al. 2012. MmpL3 is a cellular target of the antitubercular pyrrole derivative BM212. AAC 56:324-31
24. Trefzer C, et al. 2012. Benzothiazinones are suicide inhibitors of mycobacterial decapre-nylphosphoryl-ß-D-ribofuranose 2’-oxidase (DprE1). J Am Chem Soc 134:912-5
25. Menendez C, et al. 2012. Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents. Eur J Med Chem. 52:275-83
26. Neres J, et al. 2012. Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis. Sci Transl Med. 4:150ra121.
27. Udine C, et al. 2013. Phenotypic and genotypic characterisation of Burkholderia cenocepacia J2315 mutants affected in homoserine lactone and diffusible signal factor-based quorum sensing systems suggests interplay between both types of systems. PLoS One. 8:e55112.
28. Poce G, et al. 2013. Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS One. 8:e56980.
29. Perrin E, et al. 2013. A census of RND superfamily proteins in the Burkholderia genus. Future Microbiol. 8:923-37.

International patents
1. Riccardi G, Manina G, Pasca MR. 2008. An effective new drug target for the treatment of tuberculosis (PCT/EP2008/001088)
2. Riccardi G, Manina G, Pasca MR. 2008. Nitroreductase NfnB from Mycobacterium smegmatis” (PCT/EP2008/009231
Project Title:
"More Medicines for Tuberculosis" (EC-VII, 2011-2015)
"More Medicines for Tuberculosis" (EC-VII, 2011-2015)
Tuberculosis remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. Moreover, M. tuberculosis strains resistant to several drugs (MDR-TB and XDR-TB) are becoming a threat to public health worldwide. Consequently, there is an urgent necessity of new antitubercular drugs. This research is part of the project "More Medicines for Tuberculosis" (EC-VII, 2011-2015).
The study of mechanism of action and resistance of new antitubercular drugs is in progress.



Project Title:
A very promising drug against Burkholderia cenocepacia (Fibrosi Cistica 2012).
Burkholderia cenocepacia is considered one of the most serious cystic fibrosis (CF) pathogens and it causes infections in about 3.5% of CF patients worldwide. B. cenocepacia is highly resistant to antibiotics, thus prompting the need for new strategies for the control of infections.
CF patients often die because of B. cenocepacia infections. By discovering new drugs against this pathogen, we will be able to improve the treatment of lethal infections due to B. cenocepacia.
The study of mechanism of action and resistance of a new drug against B. cenocepacia is in progress.