LABORATORY MOLECULAR BIOLOGY OF MYCOBACTERIA

 

 

Head:  Assoc.Prof. Violeta Valcheva, PhD
Tel.: +359 2 979 31 61
E-mail: violeta_valcheva@mail.bg
SCOPUS, ResearchGate, Google Scholar

STAFF:

 

Laborant Ivana Glavcheva
Tel.: +359 2 979 31 61
E-mail: glavcheva.ivanaa@gmail.com

PhD student Simeon Emilov Dimitrov
Tel.: +359 2 979 31 61
E-mail: simo_vets@abv.bg

 

MAIN RESEARCH TOPICS:

Molecular epidemiology, phylogenetics and evolution of mycobacteria (DNA isolates from the Mycobacterium tuberculosis complex (Mycobacterium tuberculosis and Mycobacterium bovis).

Bioinformatic tools for analysis of mycobacteria

Screening of newly synthesized chemical compounds and natural extracts for their in vitro antibacterial activity.

 

ACHIEVEMENTS:

 

The first molecular genetic study in veterinary medicine on the genetic diversity of Mycobacterium bovis strains circulating in Bulgaria was obtained. The Information about Bulgarian Mycobacterium bovis was added to the world Mycobacterium bovis database.

 

Classical bTB M. bovis types were circulated in the northeastern region of Bulgaria, while central/Southwestern part of the country is characterized by circulation of the M. caprae type.

 

For the first time in 40 years, an in-depth complex study was carried out for the presence of paratuberculosis in deer and mouflons freely raised in hunting farms in Bulgaria. The pathoanatomical changes found for paratuberculosis were confirmed in the histological, microbiological and molecular genetic studies.

 

Over 200 new diverse structures have been synthesized, including more than 50 chiral compounds derived from the natural terpenoids (+)-camphor and (-)-fenchone. Some of their biological and pharmacological activities were screened.

 

The newly synthesized chemical compounds and their biological effect were proven by QSAR model and molecular docking.

 

Compounds with R-2-amino-1-butanol motif, camphane-linked aminoalcohols and amidodiols as well as coumarin containing hydrazide-hydrazone analogues are quite promising lead structures as future new anti-TB drug candidates suitable for further preclinical studies.

 

PROJECTS:

 

Ministry of Education and Science, Bulgarian Science Fund- 2020, KP-06-N41/3 " New ethambutol and isoniazid derivatives as potential antituberculosis drug candidates”, 2020 - 2024 ”. Project leader: Assoc. Prof, Violeta Valcheva PhD

 

Ministry of Education and Science, Bulgarian Science Fund -2019 , KP-06-N39/7 " Advancing drug discovery by synthetic modifications of natural shikimic acid, 2019 - 2024, Institute of Organic chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences , Partner organizations: The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 2024 Coordinator of the research team , Assoc. Prof, Violeta Valcheva PhD

 

Ministry of Education and Science, Bulgarian Science Fund - 2019, KP-06-N36/17 "Biological activities of Bulgarian rose oils and approach to the waste valorisation, generated during their production”. 2019 - 2023, Project leader: Assoc. Prof. Milka Mileva, PhD”,

 

Ministry of Education and Science, Bulgarian Science Fund - 2017, DN 16/12 „Genetic diversity and population structure of Mycobacterium bovis strains isolated from cattle from different regions of Bulgaria“, 2017 – 2022, Project leader: Assoc. Prof. Magdalena Bonovska, PhD

 

COST Action CA21164 (European Cooperation for Science and Technology), Towards an improvement in diagnostics and treatment strategies for TB control (ADVANCE-TB), 2022 – 2026, Participant: Assoc. Prof. Violeta Valcheva, PhD, https://www.cost.eu/actions/CA21164

 

COST Action CA18127 (European Cooperation for Science and Technology), International Nucleome Consortium 2019 – 2023Participant: Assoc. Prof. Violeta Valcheva, PhD. https://www.cost.eu/actions/CA18127

 

International Research Consortium on Tuberculosis and other Mycobacterial Diseases, Faight Against Tuberculosis in Central and Eastern Europe (FATE). Participant: Assoc. Prof. Violeta Valcheva, PhD, 2019 – 2024, https://www.fate-consortium.org/partners/university-of-warsaw/

 

Russian Science Foundation, Grant ID: 19-1500028/2019, “Development of new effective compounds against drug-resistant strains of Mycobacterium tuberculosis, according to the population structure of the pathogen”. Project leader: Anna Vyazovaya, PhD (St. Petersburg Pasteur Institute, Russia). Coordinator of the research team for The Stephan Angeloff Institute of Microbiology – BAS: Assoc. Prof. Violeta Valcheva, PhD. And for Institute of Organic Chemistry with Centre of Phytochemistry – BAS: Assoc. Prof. Georgi Dobrikov, PhD.

 

Medical University – Sofia, “ Synthesis, structural characterization, antimycobacterial activity and toxicity of new indole derivatives. Determination of their chemical stability by HPLC method“. 2017-2018, Project leader: Assoc. prof. Violina Angelova, PhD Coordinator of the research team for the The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Assoc. Prof, Violeta Valcheva PhD

 

National Diagnostic and Research Veterinary Medical Institute, Grant ID: 2.32. “A systematic study of presence paratuberculosis infection in cattle (positive or suspected in PPD tuberculin)”, Project leader: Assoc.Prof. Tanya Savova-Lalkovska. Participants: The Stephan Angeloff Institute of Microbiology, BAS: Assoc. Prof. Magdalena Bonovska, PhD, Assoc. Prof. Violeta Valcheva, PhD.

 

Patents

Invention patent: (4-(3-Hydroxyphenyl)piperazin-1-yl)(5-nitrofuran-2-yl)methanone with anti-tuberculosis activity against multi-resistant tuberculosis strain and method for its preparation. Federal Office of Intellectual Property of the Russian Federation Patent RU No. 2021133251/15.11.2021 Dobrikov G., Dogonadze M.Z., Solovyeva N.S., Vyazovaya A.A., Valcheva V., Mokrousov I.V., Zhuravlev V.Yu.

 

 

SELECTED PUBLICATIONS:

 

 

1. Valcheva, V., Perea, C., Savova-Lalkovska, T., Dimitrova, A., Radulski, L., Mokrousov, I., Bonovska, M. Mycobacterium bovis and M. caprae in Bulgaria: insight into transmission and phylogeography gained through whole-genome sequencing. BMC veterinary research, 2022. 18 (1), 1-12. https://doi.org/10.1186/s12917-022-03249-w 

    

   Slavchev, I. M., Mitrev, Y., Shivachev, B., Valcheva, V., Dogonadze, M., Solovieva, N., Dobrikov, G. M. Synthesis, Characterization and Complex Evaluation of Antibacterial Activity and Cytotoxicity of New Arylmethylidene Ketones and Pyrimidines with Camphane Skeletons. ChemistrySelect, 202 7(17), e202201339. https://doi.org/10.1002/slct.202201339 

   Angelova, V. T., Pencheva, T., Vassilev, N., K-Yovkova, E., Mihaylova, R., Petrov, B.,

    

   Valcheva, V. Development of New Antimycobacterial Sulfonyl Hydrazones and 4-Methyl-1, 2, 3-thiadiazole-Based Hydrazone Derivatives. Antibiotics, 2022. 11(5), 562. https://doi.org/10.3390/antibiotics11050562 

    

   Chimshirova, R., Popova, M., Chakir, A., Valcheva, V., Dimitrov, S., Trusheva, B., Bankova, V. Antimicrobial triterpenoids and ingol diterpenes from propolis of semi-arid region of Morocco. Molecules, 2022. 27(7), 2206. https://doi.org/10.3390/molecules27072206 

   Mileva, M, Ilieva, Y, Jovtchev, G, Gateva, S, Zaharieva, MM, Georgieva, A, Dimitrova, L, Dobreva, A, Angelova, Ts, Vilhelmova-Ilieva, N, Valcheva, V, Najdenski, H. Rose flowers—A Delicate Perfume or a Natural Healer?. Biomolecules, 2021, 11, 1, doi:https://doi.org/10.3390/biom11010127, 127-159. 

    

   Valcheva V., SavovaLalkovska T., Vyazovaya A., Dimitrova A. Bonovska M. Najdenski H First insight into phylogeography of Mycobacterium bovis and Mycobacterium caprae from cattle in Bulgaria. Infection, Genetics and Evolution, 2020, doi: 10.1016/j.meegid.2020.104240 

    

   Savova-Lalkovska T., Bonovska M., Dimitrova A., Valcheva V., Petkov Y., Hadjieva G., Najdenski H. Evaluation of classical and rapid methods for isolation and identification of Mycobacterium bovis in cattle in Bulgaria. Bulgarian Journal of Veterinary Medicine, 2019, doi: 10.15547/bjvm.2289

    

   Georgieva K., Trusheva B., Uzunova V., Stoyanova T., Valcheva V., Popova M., Bankova V. New cycloartane triterpenes from bioactive extract of propolis from Pitcairn Island. Fitoterapia, 2018, 128: 233-241. doi: 10.1016/j.fitote.20105.024.

    

   Doncheva, T., Kostova, N., Valcheva, V., Toshkovska, R., Vutov, V., Philipov, S. Hypepontine, a new quaternary alkaloid with antimicrobial properties. Natural product research, 2018, 1-7. doi:10.1080/14786412018.1495640

    

   Yanev, S., Stoyanova, T., Valcheva V., De Montellano, O. Xanthates: Metabolism by Flavoprotein-Containing Monooxygenases and Antimycobacterial Activity. Drug Metabolism and Disposition, 2018. 46(8), 1091-1095. DOI:1124/dmd.118.081984, 1091-1095 

    

   Philipova, I., Valcheva, V., Mihaylova, R., Mateeva, M., Doytchinova, I. and Stavrakov, G., Synthetic piperine amide analogues with antimycobacterial activity. Chem biology & drug design. 2017. doi: 10.1111/cbdd.13140

    

   Mokrousov, I., Chernyaeva, E., Vyazovaya, A., Skiba, Y., Solovieva, N., Valcheva, V., Levina, K., Malakhova, N., Jiao, W.W., Gomes, L.L. and Suffys, P.N., A rapid assay for detection of the epidemiologically important Central Asian/Russian strain of the Mycobacterium tuberculosis Beijing genotype. J Clin Microbiol. 2017. pii: JCM.01551-17. doi: 10.1128/JCM.01551-17

    

   Angelova, V., Valcheva, V., Pencheva, T., Voynikov, Y., Vassilev, N., Mihaylova, R., Momekov, G. and Shivachev, B., Synthesis, antimycobacterial activity and docking study of 2-aroyl-[1] benzopyrano [4, 3-c] pyrazol-4 (1H)-one derivatives and related hydrazide-hydrazones. Bioorg Med Chem Lett, 2017. 27 (13): 2996-3002. doi: 10.1016/j.bmcl.2017.05.011 

    

   Angelova V., Valcheva V, Vassilev N.G, Buyukliev R, Momekov G, Dimitrov I, Saso L, Djukic M, Shivachev B. Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-chromene and coumarin scaffold. Bioorg Med Chem Lett. 2017; 27(2): 223-227. doi: 10.1016/j.bmcl.2016.11.071.

    

   Mokrousov I, Vyazovaya A, Iwamoto T, Skiba Y, Pole I, Zhdanova S, Arikawa K, Sinkov V, Umpeleva T, Valcheva V, Alvarez Figueroa M, Ranka R, Jansone I, Ogarkov O, Zhuravlev V, Narvskaya O. Latin-American-Mediterranean lineage of Mycobacterium tuberculosis: Human traces across pathogen's phylogeography. Mol Phylogenet Evol. 2016. 99:133-143. doi: 10.1016/j.ympev.2016.03.020. 

    

    Valcheva V., Rastogi, N., Mokrousov, I. Prevalence of Latin-American-Mediterranean genetic family in population structure of Mycobacterium tuberculosis in Bulgaria. Int. J of Mycobacteriology. 2015. 4(1): 22-23; doi:10.1016/j.ijmyco.2014.10.044 

    

   Slavchev I, Dobrikov GM, Valcheva V, Ugrinova I, Pasheva E, Dimitrov V. Antimycobacterial activity generated by the amide coupling of (-)-fenchone derived aminoalcohol with cinnamic acids and analogues. Bioorg Med Chem Lett. 2014 ; 24 (21): 5030-3.

    

   Voynikov Y, Valcheva V, Momekov G, Peikov P, Stavrakov G. Theophylline-7-acetic acid derivatives with amino acids as anti-tuberculosis agents. Bioorg Med Chem Lett. 2014. pii: S0960-894X(14)00526-5. doi: 10.1016/j.bmcl.2014.05.026.

    

   Stavrakov G, Valcheva V, Philipova I, Doytchinova I Design of novel camphane-based derivatives with antimycobacterial activity. J Mol Graph Model. 2014. 51C:7-12.

    

    Petkova Z, Valcheva V, Momekov G, Petrov P, Dimitrov V, Doytchinova I, Stavrakov G, Stoyanova M. Antimycobacterial activity of chiral aminoalcohols with camphane scaffold. Eur J Med Chem. 2014. 81C:150-157.

    Dobrikov GM, Valcheva V, Nikolova Y, Ugrinova I, Pasheva E, Dimitrov V. Enantiopure antituberculosis candidates synthesized from (-)-fenchone. Eur J Med Chem. 2014. 77:243-7.

    

   Stavrakov G, Philipova I, Valcheva V, Momekov G. Synthesis and antimycobacterial activity of novel camphane-based agents. Bioorg Med Chem Lett. 2014. 24(1):165-7.

    

   Stavrakov G, Valcheva V, Philipova I, Doytchinova I. Novel camphane-based anti-tuberculosis agents with nanomolar activity. Eur J Med Chem. 2013. 70:372-9.

    

    Dobrikov GM, Valcheva V, Nikolova Y, Ugrinova I, Pasheva E, Dimitrov V. Efficient synthesis of new (R)-2-amino-1-butanol derived ureas, thioureas and acylthioureas and in vitro evaluation of their antimycobacterial activity. Eur J Med Chem. 2013. 63: 468-73.

    

    Dobrikov GM, Valcheva V, Stoilova-Disheva M, Momekov G, Tzvetkova P, Chimov A, Dimitrov V. Synthesis and in vitro antimycobacterial activity of compounds derived from (R)- and (S)-2-amino-1-butanol - The crucial role of the configuration. Eur J Med Chem. 2012. 48:45-56

    

    Valcheva V., Mokrousov I., Panaiotov S., Bachiiska E., Zozio T., Sola C., Markova N., Rastogi N. Bulgarian specificity and controversial phylogeography of Mycobacterium tuberculosis spoligotype ST125_BGR. FEMS Immunol Med Microbiol. 2010. 59: 90-99.

    

   Valcheva V., Mokrousov I., Narvskaya O., Rastogi N., Markova N. Utility of new 24-locus variable-number tandem-repeat typing for discriminating Mycobacterium tuberculosis clinical

   isolates collected in Bulgaria. J. Clin. Microbiol. 2008.46: 3005-3011

    

   Valcheva V., Mokrousov I., Narvskaya O., Rastogi N., Markova N. Molecular snapshot of drug-resistant and drug-susceptible Mycobacterium tuberculosis strains circulating in Bulgaria. Infect. Genet. Evol. 2008. 8: 657-663.

    

   Valcheva V., Mokrousov I., Rastogi N., Narvskaya O., Markova N. Molecular characterization of Mycobacterium tuberculosis isolates from different regions of Bulgaria. J Clin Microbiol. 2008. 46:1014-1018.