Edda De Rossi
Edda De Rossi
affiliation: Università di Pavia
research area(s): Molecular Biology, Chemical Biology
Course: Genetics, Molecular and Cellular Biology
University/Istitution: Università di Pavia
Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia - Via Ferrata 1, 27100 Pavia (Italy)
Phone: +39 0382985561; Fax: +39 0382528496; E-mail: edda.derossi@unipv.it

1992: PhD Degree in Molecular Biotechnology (University of Piacenza); 1984: “Laurea” in Biological Science (University of Pavia).

Since 2005: Associate Professor of Microbiology, at the Department of Genetics and Microbiology, University of Pavia. 1998-2004: Ricercatore (Assistant Professor) at the Department of Genetics and Microbiology, University of Pavia; 1995: Stage in the laboratory of Génétique Moléculaire Bactérienne (Dr. Cole - Institute Pasteur, Paris, France); 1992-1998: Technician at the Department of Genetics and Microbiology, University of Pavia.
She is Member of the American Society of Microbiology and the Italian Microbiology and Microbial Biotechnology Association, referee for several international scientific journals (Journal of Antimicrobial Chemotherapy, Journal of Bacteriology, Antimicrobial Agents and Chemotherapy, Journal of Clinical Microbiology, FEMS Microbiology Letters) and granting agencies.

Since 2005: Associate Professor of Microbiology (Biology degree), Applied Microbiology (Biotechnology degree) and Microbiological Analyses (Experimental and Applied Biology Specialistic degree), University of Pavia. 1999-2004: non-tenure Professor of General Microbiology (1999-2002) and Applied Microbiology (2000-2004), University of Pavia.

1) Identification of the cellular targets for new drugs in Mycobacterium tuberculosis
2) Efflux pumps and multidrug resistance in mycobacteria

Prof. De Rossi has a recognized experience in the study of antibiotic resistance mechanisms (especially those based on efflux pumps), and in genetics and molecular biology of mycobacteria. She has experience in mycobacterial genome sequencing, DNA libraries construction and screening, mycobacterial gene inactivation, and general gene cloning. She is dealing with the target identification of new promising antitubercular drugs by microbiological, genetic and molecular approaches.

Prof. De Rossi has obtained grants from Research program FAR, Integrated Action Italy-Spain, V EC Framework Programme, Fondazione Cariplo, and MIUR-PRIN-2005 and 2008.
1) Identification and characterization of the cellular target of pyrrole derivatives
BM212, belonging to a series of pyrrole derivatives, shows a potent activity against M. tuberculosis, non-tuberculosis mycobacteria, such as M. avium, and drug-resistant clinical isolates of M. tuberculosis as well as on intracellular bacilli. On the basis of these results, BM212 was considered the lead compound of this new class of derivatives and one of the promising future antimycobacterial drug. Since the target of BM212 was unknown, the objective of this work is the identification and characterization of the cellular target of the compound in M. smegmatis. To this aim, M. smegmatis mutants resistant to BM212 have been isolated. To identify the gene(s) responsible for the resistance, a genomic library of one of these mutants has been constructed and screened for BM212 resistance. Two point mutations, giving rise to amino acid substitutions, have been identified in the mmpL3 gene coding for the membrane protein MmpL3 with unknown function. Since mutations in the target gene are responsible for drug resistance, the MmpL3 protein seems to be the cellular target of BM212. The members of the MmpL family belong to the RND family of efflux pumps, membrane proteins of Gram negative bacteria, able to extrude out of the cell structurally and functionally unrelated compounds. Microbiological assays and uptake/efflux experiments demonstrated that MmpL3 does not extrude BM212 out of the cell meaning that the protein is not an efflux pump but the cellular target of BM212. Given the identification of mutations in mmpL3 as responsible for resistance to BM212, the sequence of the mmpL3 gene from BM212-resistant M. bovis BCG and M. tuberculosis isolates has been determined. All revealed substitutions non-synonymus mmpL3 mutations.
By further characterization of the MmpL3 protein, it will be possible to obtain more insights to design new and more effective antimycobacterial BM212 derivatives.

2) Identification and characterization of the cellular target of new antitubercular molecules
This research is part of the project "New Medicines for Tuberculosis – NM4TB" funded by EC-VI FP. The cellular target of a new drug, belonging to the class of benzothiazinones (BTZ-NO2) has been identified in the M. tuberculosis Rv3790 enzyme.. Both the over-expression and the mutation of a cysteine residue at the C-terminal of Rv3790 are responsible for high resistance levels to BTZ-NO2. It has been previously demonstrated that Rv3790 works in concert with Rv3791 in the biosynthesis of arabinogalactan, an important component of mycobacterial cell wall. In particular they are involved in the formation of decaprenyl-P-arabinose (DPA), a fundamental precursor in the arabinan synthesis. By enzymatic assay it was confirmed that the synthesis of DPA is inhibited in the presence of BTZ-NO2 in wild type mycobacterial strains but not in BTZ-NO2 resistant mutants.
The M. smegmatis NfnB nitroreductase, able to convert the original effective molecule BTZ-NO2 into its less active derivative BTZ-NH2 has been also identified. By further characterization of the Rv3790 and NfnB proteins, it will be possible to obtain more insights to design new and more effective benzothiazinones derivatives.
A new project funded by EC-VII FP (More Medicines for Tuberculosis – MM4TB) started in February 2011 with the aim to identify new targets for new antitubercular drugs.
-Pasca MR, Guglierame P, Arcesi F, Bellinzoni M, De Rossi E, Riccardi G (2004) Rv2686c-2687c-2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob Agents Chemother 48:3175-8.
-Bellinzoni M, Buroni S, Pasca MR, Guglierame P, Arcesi F, De Rossi E, Riccardi G (2005) Glutamine amidotransferase activity of NAD+ synthetase from Mycobacterium tuberculosis depends on an amino-terminal nitrilase domain. Res Microbiol 156:173-7.
-Pasca MR, Guglierame P, De Rossi E, Zara F, Riccardi G (2005) The mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob Agents Chemother 49:4775-7.
-De Rossi E, Ainsa JA, Riccardi G (2006) Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol Rev 30:36-52.
-Ramón-García S, Martín C, Aínsa JA, De Rossi E (2006) Characterization of tetracycline resistance mediated by the efflux pump Tap from Mycobacterium fortuitum. J Antimicrob Chemother 57:252-9.
-Guglierame P, Pasca MR, De Rossi E, Buroni S, Arrigo P, Manina G, Riccardi G (2006) Efflux pump genes of the resistance-nodulation-division family in Burkholderia cenocepacia genome. BMC Microbiol 6:66-79.
-Buroni S, Manina G, Guglierame P, Pasca MR, Riccardi G, De Rossi E (2006) LfrR is a repressor that regulates expression of the efflux pump LfrA in Mycobacterium smegmatis. Antimicrob Agents Chemother 50:4044-52.
-Ramón-García S, Martín C, De Rossi E, Aínsa JA (2007) Contribution of the Rv2333c efflux pump (the Stp protein) from Mycobacterium tuberculosis to intrinsic antibiotic resistance in M. bovis BCG. J Antimicrob Chemother 59:544-7.
-Biava M, Porretta GC, Poce G, De Logu A, Saddi M, Meleddu R, Manetti F, De Rossi E, Botta M (2008) 1,5-diphenyl pyrrole derivatives as antimycobacterial agents. Probing the influence on antimycobacterial activity of lipophilic substituents at the phenyl rings. J Med Chem 51:3644-8.
-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 (2009) Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324:801-4.
-Bellinzoni M, Buroni S, Schaeffer F, Riccardi G, De Rossi E, Alzari PA (2009) Structural plasticity and distinct drug-binding modes of LfrR, a mycobacterial efflux pump regulator. J Bacteriol 191:7531-7.
-Biava M, Porretta GC, Poce G, De Logu A, Meleddu R, De Rossi E, Manetti F, Botta M (2009) 1,5-Diaryl-2-ethyl pyrrole derivatives as antimycobacterial agents: design, synthesis, and microbiological evaluation. Eur J Med Chem 44:4734-8.
-Manina G, Bellinzoni M, Pasca MR, Neres J, Milano A, de Jesus AL, Ribeiro L, Buroni S, Skovierová 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 (2010) Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance. Mol Microbiol 77:1172-85.
-Manina G, Pasca MR, Buroni S, De Rossi E, Riccardi G (2010) Decaprenylphosphoryl-beta-D-ribose 2'-epimerase from Mycobacterium tuberculosis is a magic drug target. Curr Med Chem 17:3099-108.
-La Rosa V, Poce G, Ortiz Canseco J, Buroni S, 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 EJ, De Rossi E (2012) MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob Agents Chemother 56:324-31.
-Ramón-García S, Mick V, Dainese E, Martín C, Thompson CJ, De Rossi E, Manganelli R, Aínsa JA (2012) Functional and genetic characterization of the Tap efflux pump in Mycobacterium bovis BCG. Antimicrob Agents Chemother 56:2074-83.
-Neres J., Pojer F., Molteni E., Chiarelli L.R., Dhar N., Boy-Röttger S., Buroni S., Fullam E., Degiacomi G., Lucarelli A.P., Read R.J., Zanoni G., Edmondson D.E., De Rossi E., M.R. Pasca, McKinney J.D., Dyson P.J., Riccardi G., Mattevi A., Cole S.T., Binda C. (2012) Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis. Science Trans. Med. 4:150ra121.
-Poce G., Bates R.H., Alfonso S., Cocozza M., Porretta G.C., Ballell L., Rullas J., Ortega F., De Logu A., Agus E., La Rosa V., Pasca M.R., De Rossi E., Wae B., Franzblau S.G., Manetti F., Botta M., Biava M. (2013) Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS One. 8(2):e56980.
No projects are available to students for the current accademic year.