Curriculum vitae et studiorum of Maria Rosalia Pasca

Curriculum vitae et studiorum of Maria Rosalia Pasca
DATE OF BIRTH: 11st July 1971
EDUCATION
· 21/03/1997: Degree in Natural Sciences (110/110), University of Bari, Italy.
· 04/02/2002: PhD in Genetics and Molecular Evolution, University of Bari, Italy.
ACADEMIC POSITION
· From 1st October 2006: Researcher in Microbiology (BIO/19), Department of Biology and
Biotechnology “Lazzaro Spallanzani”, University of Pavia, Italy.
· February 2014: National scientific qualification for Associate Professor (BIO/19).
PREVIOUS PROFESSIONAL EXPERIENCES
· 1998-2002: PhD student in the Laboratory of Genetics of Microorganisms, University of
Bari, Italy (supervisor: Prof. M.S. Ciampi).
· 12/1998-01/1999: Stages in the Laboratory of Molecular Genetics, University of Camerino,
Italy (supervisor: Prof. C. Gualerzi).
· 1999, 2001: Stages in the Laboratory of Molecular Genetics, University of Ancona, Italy
(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, Italy (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,
Italy.
· 2008-2012: Professor of the course "Pathogen Identifications" (3 CFU), Master degree in
Experimental and Applied Biology (Bioanalysis course), University of Pavia, Italy.
· 2009-2010: Professor of the course “Microbiological techniques” (6 CFU), Degree in
Biological Sciences (Industrial course), University of Pavia, Italy.
· 2009-2010: Professor of the course “Microbiological techniques” (20 h), Speciality School
in Microbiology and Virology, University of Pavia, Italy.
· 2010-11: Professor of the course “Laboratory of cellular Methodologies (1 CFU), Degree in
Biological Sciences (Biomolecular course), University of Pavia, Italy.
· 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, Italy.
· From 2013-2014: Professor of the course “General Microbiology” (6CFU), Master degree in
· Environmental Engineering, University of Pavia, Italy.
· From 2013-12: Professor of the course “Didactics and Laboratory of Biology” (2 CFU) in
Speciality school “PAS (Percorsi Abilitanti Speciali)” for 059 and 060 classes.
· From 2013-2014: Coordinator of the following Speciality schools “PAS (Percorsi Abilitanti
Speciali)” and “TFA (Tirocinio formative attivo)” for 060 class.
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·
From 2008: member staff of PhD School in Genetics, Molecular and Cellular biology,
University of Pavia, Italy (Coordinator: Prof. Antonio Torroni).
Supplementary didactical Activities
· 1997-2002: laboratory assistance to students for theses in Natural Sciences, University of
Bari, Italy.
· 2002-2010: Microbiology laboratory lessons to students for Biotechnology degree,
University of Pavia, Italy.
· From 2002: collaboration to General Microbiology exams and theses for the degrees in
Biological Sciences and Biotechnology (Prof. G. Riccardi), respectively, University of
Pavia, Italy.
· From 2006, supervisor of theses for Degree in Biological Sciences and Master degree in
Experimental and Applied Biology , University of Pavia, Italy.; From 2006, supervisor of
theses for Degree and Master degree in Biotechnology, University of Pavia, Italy.
· From 2010-2011. Supervisor of PhD thesis, School in Genetics, Molecular and Cellular
biology, University of Pavia, Italy.
· 3-9/06/2009: Organiser of PhD course: “Applications of "-omics" in microbiological field”.
· 11-27/04/2009: Organiser of PhD course: “Emerging bacterial and viral pathogens”.
SUMMARY OF THE MAJOR POINTS OF THE RESEARCH WORK
1. Role of efflux pumps in M. tuberculosis drug resistance.
In this field, we identified and characterized some efflux pumps responsible for drug resistance in
M. tuberculosis.
2. Identification of mechanism of action and of resistance for the new antitubercular class
Benzothiazinones.
Tuberculosis remains the leading cause of mortality due to a bacterial pathogen, M. tuberculosis.
Moreover, M. tuberculosis strains resistant to several drugs (MDR-TB, XDR-TB, and TDR-TB) are
becoming a threat to public health worldwide. Consequently, there is an urgent necessity of new
anti-TB drugs.
We have identified the target of the benzothiazinones (BTZ), very effective drugs against M.
tuberculosis, that is DprE1, an enzyme involved in the biosynthesis of arabinogalactan, a cell wall
component (PCT/EP2008/001088). We have characterized 240 M. tuberculosis clinical isolates and
verified that the BTZ are effective also against MDR and XDR strains. Recently we are able to
solve the crystallographic structure of M. smegmatis DprE1 alone and in combination with BTZ.
Moreover the physiologic role of DprE1 has been better defined.
We have also identified a Mycobacterium smegmatis nitroreductase, NfnB, able to convert the
effective molecule BTZ-NO2 into its less active derivative BTZ-NH2 (PCT/EP2008/009231).
We demonstrated that another class of antitubercular drugs, the Dinitrobenzamides (DNB) has as
target DprE1 and the same mechanism of resistance of BTZ involving NfnB enzyme.
Recently another antitubercular drug hitting DprE1 target has been identified; we also characterized
a new mechanism of inactivation of this new compound.
Collaborations: Cole ST (EPFL, Lausanne, Switzerland), Makarov V (Bakh Institute of
Biochemistry, Russian Academy of Science, Moscow, Russia).
3. Searching for new antitubercular drugs and new targets.
With the aim to find new antitubercular drugs, we tested some triazole derivatives as inhibitors of
InhA and antitubercular agents; we found that these new compounds have a good activity against
M. tuberculosis.
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The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against M. tuberculosis
sensitive and resistant clinical isolates. We found MmpL3 protein as cellular target of BM212 and
its derivatives.
In the last European project MM4TB (VII FP), the study of mechanism of action and resistance of
new possible antitubercular compounds is in progress. These agents are natural and of new
synthesis. Until now, we identified the mechanism of action of some new compounds and new
cellular targets are under investigation (not published data).
We identified a singular mechanism of activation of new antitubercular drugs mediated by a
thioredoxin-like enzyme.
Collaborations: Cole ST (EPFL, Lausanne, Switzerland), Makarov V (Bakh Institute of
Biochemistry, Russian Academy of Science, Moscow, Russia), Baltas M (CNRS, Toulouse,
France).
4. A very promising drug against Burkholderia cenocepacia.
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.
We found a new drug active against this pathogen and we are characterizing its mechanisms of
action and resistance. At the same time we are testing new compounds against this pathogen
Collaborations: Makarov V (Bakh Institute of Biochemistry, Russian Academy of Science,
Moscow, Russia.
EXPERTISE
Tuberculosis, Mycobacterium tuberculosis, Bacterial diseases, Bacterial pathogens, Mycobacteria,
Drug discovery, Pathogenesis, Burkholderia cepacia complex, Burkholderia infection, Candida
albicans, Microbiology, Drug resistance, Drug target.
LECTURE
Pasca M. R. (28/05/2009) “New drugs and a new cellular target against tuberculosis”. I.N.M.I. "L.
Spallanzani" I.R.C.C.S., Roma, Italy.
REFEREE'S ACTIVITY
She has been referee for: Annals of Microbiology, BMC infectious diseases, BMC Microbiology,
Central European Journal of Biology, International Journal of Medical Sciences, IUBMB Life,
Journal of Antimicrobial chemotherapy, Journal of enzyme inhibition and medicinal chemistry,
Expert Review of Anti-Infective Therapy, Microbial drug resistance, Tuberculosis.
PERSONAL BIBLIOGRAPHY
She is author of 36 peer-reviewed articles, 4 chapters for books, 2 international patent applications
and several international and national communications to congresses (from SCOPUS: h index: 15;
Citations: 764).
PUBLICATIONS
1. Federici F, Vitali B, Gotti R, Pasca MR, Gobbi S, Peck AB, Brigidi P. Characterization and
heterologous expression of the oxalyl-CoA decarboxylase gene from Bifidobacterium lactis.
Antimicrob Agents Chemother. 2004;48(8):3175-8.
2. Pasca MR, Guglierame P, Arcesi F, Bellinzoni M, De Rossi E, Riccardi G. Rv2786c2687c-2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Appl
Environ Microbiol. 2004;70(9):5066-73.
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3. Bellinzoni M, Buroni S, Pasca MR, Guglierame P, Arcesi F, De Rossi E, Riccardi G.
Glutamine amidotransferase activity of NAD+ synthetase from Mycobacterium tuberculosis
depends on an amino-terminal nitrilase domain. Res Microbiol. 2005;156(2):173-7.
4. Pasca MR, Guglierame P, De Rossi E, Zara F, Riccardi G. The mmpL7 gene of
Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium
smegmatis. Antimicrob Agents Chemother. 2005;49(11):4775-7.
5. Guglierame P, Pasca MR, De Rossi E, Buroni S, Arrigo P, Manina G, Riccardi G. Efflux
pump genes of the resistance-nodulation-division family in Burkholderia cenocepacia
genome. BMC Microbiol. 2006;6:66.
6. Buroni S, Manina G, Guglierame P, Pasca MR, Riccardi G, De Rossi E. LfrR is a repressor
that regulates expression of the efflux pump LfrA in Mycobacterium smegmatis. Antimicrob
Agents Chemother. 2006;50(12):4044-52.
7. Maciag A, Dainese E, Rodriguez MG, Milano A, Provvedi R, Pasca MR, Smith I, Palù G,
Riccardi G, Manganelli R. Global analysis of Mycobacterium tuberculosis FurB regulon. J
Bacteriol. 2007;189(3):730-40.
8. Riccardi G, Milano A, Pasca MR, Nies DH. Genomic analysis of zinc homeostasis in
Mycobacterium tuberculosis. FEMS Microbiol Lett. 2008;287(1):1-7.
9. Milano A, Pasca MR, Provvedi R, Lucarelli AP, Manina G, Ribeiro AL, Manganelli R,
Riccardi G. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpL5MmpS5 efflux system. Tuberculosis (Edinb). 2009;89(1):84-90.
10. § Makarov V, Manina G, Mikusova K, Möllmann U, Ryabova O, Saint-Joanis B, Dhar N,
Pasca MR, Buroni S, Lucarelli AP, Milano A, De Rossi E, Belanova M, Bobovska A,
Dianiskova P, Kordulakova J, Sala C, Fullam E, Schneider P, McKinney JD, Brodin P,
Christophe T, Waddell S, Butcher P, Albrethsen J, Rosenkrands I, Brosch R, Nandi V,
Bharath S, Gaonkar S, Shandil RK, Balasubramanian V, Balganesh T, Tyagi S, Grosset J,
Riccardi G, Cole ST. Benzothiazinones kill Mycobacterium tuberculosis by blocking
arabinan synthesis. Science. 2009;324(5928):801-4.
11. Riccardi G, Pasca MR, Buroni S. Mycobacterium tuberculosis: drug resistance and future
perspectives. Future Microbiol. 2009;4(5):597-614.
12. Dalla Valle C, Pasca MR, De Vitis D, Capra Marzani F, Emmi V, Marone P. Control of
MRSA infection and colonisation in an intensive care unit by GeneOhm MRSA assay and
culture methods. BMC Infect Dis. 2009;9:137.
13. Buroni S, Pasca MR, Flannagan RS, Bazzini S, Milano A, Bertani I, Venturi V, Valvano
MA, Riccardi G. Assessment of three Resistance-Nodulation-Cell Division drug efflux
transporters of Burkholderia cenocepacia in intrinsic antibiotic resistance. BMC Microbiol.
2009;9:200.
14. Pasca MR, Degiacomi G, Ribeiro AL, Zara F, De Mori P, Mirrione M, Brerra R, Pagani L,
Pucillo L, Troupioti P, Makarov V, Cole ST, Riccardi G. Clinical isolates of Mycobacterium
tuberculosis in four european hospitals are uniformly susceptible to benzothiazinones.
Antimicrob Agents Chemother. 2010;54(4):1616-8.
15. Perrin E, Fondi M, Papaleo MC, Maida I, Buroni S, Pasca MR, Riccardi G, Fani R.
Exploring the HME and HAE1 efflux systems in the genus Burkholderia. BMC Evol Biol.
2010;10:164.
16. Manina G, Bellinzoni M, Pasca MR, Neres J, Milano A, de Jesus Lopes Ribeiro AL, Buroni
S, Škovierová H, Dianišková P, Mikušová K, Marák J, Makarov V, Giganti D, Haouz A,
Lucarelli AP, Degiacomi G, Piazza A, Chiarelli LR, De Rossi E, Salina E, Cole ST, Alzari
PM, Riccardi G. Biological and structural characterization of the Mycobacterium smegmatis
nitroreductase NfnB, and role in benzothiazinone resistance Mol Microbiol.
2010;77(5):1172-85.
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17. Manina G, Pasca MR, Buroni S, De Rossi E, Riccardi G. Decaprenylphosphoryl-β-D-ribose
2’-epimerase from Mycobacterium tuberculosis is a magic drug target. Curr Med Chem.
2010;17(27):3099-108.
18. Lucarelli AP, Buroni S, Pasca MR, Rizzi M, Valentini G, Riccardi G, Chiarelli LR.
Mycobacterium tuberculosis phosphoribosyl pyrophosphate synthetase: biochemical
features of a crucial enzyme for mycobacterial cell wall biosynthesis. PLoS One.
2010;5(11):e15494.
19. Bazzini S, Udine C, Sass A, Pasca MR, Longo F, Emiliani G, Fondi M, Perrin E, Decorosi
F, Viti C, Giovannetti L, De Rossi E, Leoni L, Fani R, Riccardi G, Mahenthiralingam E,
Buroni S. Deciphering the role of RND efflux transporters in Burkholderia cenocepacia.
PLoS One. 2011;6(4):e18902.
20. Menendez C, Gau S, Lherbet C, Rodriguez F, Inard C, Pasca MR, Baltas M. Synthesis and
biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents.
Eur J Med Chem. 2011;46(11):5524-31.
21. de Jesus Lopes Ribeiro AL, Degiacomi G, Ewann F, Buroni S, Incandela ML, Chiarelli LR,
Mori G, Kim J, Contreras-Dominguez M, Park YS, Han SJ, Brodin P, Valentini G, Rizzi M,
Riccardi G, Pasca MR. Analogous mechanisms of resistance to benzothiazinones and
dinitrobenzamides in Mycobacterium smegmatis. PLoS One. 2011;6(11):e26675.
22. Pasca MR, Dalla Valle C, de Jesus Lopes Ribeiro AL, Buroni S, Papaleo MC, Bazzini S,
Udine C, Incandela ML, Daffara S, Fani R, Riccardi G, Marone P. Evaluation of
fluoroquinolone resistance mechanisms in Pseudomonas aeruginosa MDR clinical isolates.
Microb Drug Resist. 2012;18(1):23-32.
23. La Rosa V, Poce G, Ortiz-Canseco J, Buroni S,1 Pasca MR, Biava M, Raju RM, Porretta
GC, Alfonso S, Battilocchio C, Javid B, Sorrentino F, Ioerger TR, Sacchettini JC, Manetti F,
Botta M, De Logu A, Rubin E, De Rossi E. MmpL3 is a cellular target of the antitubercular
pyrrole derivative BM212. Antimicrob Agents Chemother. 2012;56(1):324-31.
24. Trefzer C, Skovierová H, Buroni S, Bobovská A, Nenci S, Molteni E, Pojer F, Pasca MR,
Makarov V, Cole ST, Riccardi G, Mikušová K, Johnsson K. Benzothiazinones are suicide
inhibitors of mycobacterial decapre-nylphosphoryl-ß-D-ribofuranose 2’-oxidase (DprE1). J
Am Chem Soc. 2012;134(2):912-5.
25. Menendez C, Chollet A, Rodriguez F, Inard C, Pasca MR, Lherbet C, Baltas M. Chemical
synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and
antituberculosis agents. Eur J Med Chem. 2012;52:275-83.
26. Neres J, Pojer F, Molteni E, Chiarelli L, Dhar N, Boy-Röttger S, Buroni S, Fullam E,
Degiacomi G, Lucarelli AP, Read RJ, Zanoni G, De Rossi E, Pasca MR, Riccardi G,
Mattevi A, Dyson PJ, Cole ST, Binda C. Structural basis for benzothiazinone-mediated
killing of Mycobacterium tuberculosis. Sci Transl Med. 2012;4(150):150ra121.
27. Udine C, Brackman G, Bazzini S, Buroni S, Van Acker H, Pasca MR, Riccardi G, Coenye
T. 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. 2013;8(1):e55112.
28. Poce G, Bates RH, Alfonso S, Cocozza M, Porretta GC, Ballell L, Rullas J, Ortega F, De
Logu A, Agus E, La Rosa V, Pasca MR, De Rossi E, Wae B, Franzblau SG, Manetti F,
Botta M, Biava M. Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute
murine model of tuberculosis infection. PLoS One. 2013;8(2):e56980.
29. Perrin E, Fondi M, Papaleo MC, Maida I, Emiliani G, Buroni S, Pasca MR, Riccardi G,
Fani R. A census of RND-superfamily proteins in the Burkholderia genus. Future Microbiol.
2013; 8:923-37.
30. Menendez C, Rodriguez F, de Jesus Lopes Ribeiro AL, Zara F, Frongia C, Lobjoise V,
Saffon N, Pasca MR, Lherbet C, Baltas M. Synthesis and Evaluation of α-ketotriazoles and
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α,β-diketotriazoles as inhibitors of Mycobacterium tuberculosis. Eur J Med Chem. 2013 Jul
8;69C:167-173.
31. Incandela ML, Perrin E, Fondi M, de Jesus Lopes Ribeiro AL, Mori G, Moiana A,
Gramegna M, Fani R, Riccardi G, Pasca MR. DprE1, a new taxonomic marker in
mycobacteria. FEMS Microbiol Lett. 2013 Nov;348(1):66-73.
32. Riccardi G, Pasca MR, Chiarelli LR, Manina G, Mattevi A, Binda C. The DprE1 enzyme,
one of the most vulnerable targets of Mycobacterium tuberculosis. Appl Microbiol
Biotechnol. 2013 Oct;97(20):8841-8.
33. Matviiuk T, Rodriguez F, Saffon N, Mallet-Ladeira S, Gorichko M, de Jesus Lopes Ribeiro
AL, Pasca MR, Lherbet C, Voitenko Z, Baltas M. Design, chemical synthesis of 3-(9Hfluoren-9-yl)pyrrolidine-2,5-dione derivatives and biological activity against enoyl-ACP
reductase (InhA) and Mycobacterium tuberculosis. Eur J Med Chem. 2013 Oct 2;70C:3748.
34. Matviiuk T, Mori G, Lherbet C, Rodriguez F, Pasca MR, Gorichko M, Guidetti B,
Voitenko Z, Baltas M. Synthesis of 3-heteryl substituted pyrrolidine-2,5-diones via catalytic
Michael reaction and evaluation of their inhibitory activity against InhA and Mycobacterium
tuberculosis. Eur J Med Chem. 2014 Jan;71:46-52.
35. Naik M, Humnabadkar V, Tantry SJ, Panda M, Narayan A, Guptha S, Panduga V,
Manjrekar P, Jena LK, Koushik K, Shanbhag G, Jatheendranath S, Manjunatha MR, Gorai
G, Bathula C, Rudrapatna S, Achar V, Sharma S, Ambady A, Hegde N, Mahadevaswamy J,
Kaur P, Sambandamurthy VK, Awasthy D, Narayan C, Ravishankar S, Madhavapeddi P,
Reddy J, Prabhakar K, Saralaya R, Chatterji M, Whiteaker J, McLaughlin B, Chiarelli LR,
Riccardi G, Pasca MR, Binda C, Neres J, Dhar N, Signorino-Gelo F, McKinney JD,
Ramachandran V, Shandil R, Tommasi R, Iyer PS, Narayanan S, Hosagrahara V, Kavanagh
S, Dinesh N, Ghorpade SR. 4-Aminoquinolone piperidine amides: noncovalent inhibitors of
DprE1 with long residence time and potent antimycobacterial activity. J Med Chem. In
press.
36. Albesa-Jové D, Chiarelli LR, Makarov V, Pasca MR, Urresti S, Mori G, Salina E, Vocat A,
Comino N, Mohorko E, Ryabova S, Pfieiffer B, Lopes Ribeiro AL, Rodrigo-Unzueta A,
Tersa M, Zanoni G, Buroni S, Altmann KH, Hartkoorn RC, Glockshuber R, Cole ST,
Riccardi G, Guerin ME. Rv2466c mediates the activation of TP053 to kill replicating and
non-replicating Mycobacterium tuberculosis. ACS Chem Biol. In press.
§ THIS ARTICLE HAS BEEN CITED AS ONE OF KEY ARTICLES IN 2009 (SEE: NATURE
MEDICINES 15: 1349).
International patents
1. Riccardi G, Manina G, Pasca MR. 2008. An effective new drug target for the treatment of
tuberculosis” (PCT/EP2008/001088) (sold to Sentinel Diagnostics).
2. Riccardi G, Manina G, Pasca MR. 2008. Nitroreductase NfnB from Mycobacterium
smegmatis” (PCT/EP2008/009231).
Books
1. Buroni S, Riccardi G, Pasca MR. 2012. Fighting against resistant strains: the case of
benzothiazinones and dinitrobenzamides. Capitolo per il libro: “Mycobacterium
tuberculosis/Book 2”. InTech Press.
2. Pasca MR, Riccardi G, Buroni S. 2013. Mycobacterium tuberculosis efflux pumps: an
update. Capitolo 8 per il libro: “Microbial Efflux Pumps: Current Research”. Horizon
Scientific Press Ltd.
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3. de Jesus Lopes Ribeiro AL, Pasca MR, Riccardi G. 2013. New medicines against
tuberculosis. Capitolo per il libro: “Tuberculosis: Risk Factors, Drug Resistance and
Treatment”. Nova Science Publishers, Inc.
4. Bazzini S, Buroni S, Udine C, Pasca MR, Riccardi G. 2014. Molecular basis for
antibiotic resistance in the genus Burkholderia. Capitolo per il libro: “Burkholderia:
From Genomes to Function” Calster Academic Press.
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