Publicação
Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants
| Resumo: | We performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 was used for in vitro selection of spontaneous resistant mutants. The same mutations in six genes were detected in bacterial cultures grown under increased concentrations of 11 (2×, 4×, 8× MIC). The mutant positions were presented as mixed wild type and mutant alleles while increasing the concentration of the compound led to the semi-proportional and significant increase in mutant alleles. The identified genes belong to different categories and pathways. Some of them were previously reported as mediating drug resistance or drug tolerance, and counteracting oxidative and nitrosative stress, in particular: Rv0224c, fbiC, iniA, and Rv1592c. Gene-set interaction analysis revealed a certain weak interaction for gene pairs Rv1592–Rv1639c and Rv1592–Rv0224c. To conclude, this study experimentally demonstrated a multifaceted primary genetic response of M. tuberculosis to the action of nitrofurans. All three 11-treated subcultures independently presented the same six SNPs, which suggests their non-random occurrence and likely causative relationship between compound action and possible resistance mechanism. |
|---|---|
| Autores principais: | Mokrousov, Igor |
| Outros Autores: | Slavchev, Ivaylo; Solovieva, Natalia; Dogonadze, Marine; Vyazovaya, Anna; Valcheva, Violeta; Masharsky, Aleksey; Belopolskaya, Olesya; Dimitrov, Simeon; Zhuravlev, Viacheslav; Portugal, Isabel; Perdigão, João; Dobrikov, Georgi M. |
| Assunto: | nitrofuranyl amides mycobacterium tuberculosis spontaneous mutagenesis whole-genome sequencing |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| _version_ | 1866810414581415936 |
|---|---|
| author | Mokrousov, Igor |
| author2 | Slavchev, Ivaylo Solovieva, Natalia Dogonadze, Marine Vyazovaya, Anna Valcheva, Violeta Masharsky, Aleksey Belopolskaya, Olesya Dimitrov, Simeon Zhuravlev, Viacheslav Portugal, Isabel Perdigão, João Dobrikov, Georgi M. |
| author2_role | author author author author author author author author author author author author |
| author_facet | Mokrousov, Igor Slavchev, Ivaylo Solovieva, Natalia Dogonadze, Marine Vyazovaya, Anna Valcheva, Violeta Masharsky, Aleksey Belopolskaya, Olesya Dimitrov, Simeon Zhuravlev, Viacheslav Portugal, Isabel Perdigão, João Dobrikov, Georgi M. |
| author_role | author |
| contributor_name_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Mokrousov, Igor\",\"Person.identifier.orcid\":\"0000-0001-5924-0576\"},{\"Person.name\":\"Slavchev, Ivaylo\"},{\"Person.name\":\"Solovieva, Natalia\"},{\"Person.name\":\"Dogonadze, Marine\"},{\"Person.name\":\"Vyazovaya, Anna\"},{\"Person.name\":\"Valcheva, Violeta\"},{\"Person.name\":\"Masharsky, Aleksey\"},{\"Person.name\":\"Belopolskaya, Olesya\",\"Person.identifier.orcid\":\"0000-0003-2002-4192\"},{\"Person.name\":\"Dimitrov, Simeon\"},{\"Person.name\":\"Zhuravlev, Viacheslav\",\"Person.identifier.orcid\":\"0000-0001-6906-6225\"},{\"Person.name\":\"Portugal, Isabel\",\"Person.identifier.orcid\":\"0000-0002-7843-0006\"},{\"Person.name\":\"Perdigão, João\",\"Person.identifier.orcid\":\"0000-0002-0339-1305\"},{\"Person.name\":\"Dobrikov, Georgi M.\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Mokrousov, Igor Slavchev, Ivaylo Solovieva, Natalia Dogonadze, Marine Vyazovaya, Anna Valcheva, Violeta Masharsky, Aleksey Belopolskaya, Olesya Dimitrov, Simeon Zhuravlev, Viacheslav Portugal, Isabel Perdigão, João Dobrikov, Georgi M. |
| datacite.date.Accepted.fl_str_mv | 2022-09-12T00:00:00Z |
| datacite.date.available.fl_str_mv | 2023-08-17T17:03:52Z |
| datacite.date.embargoed.fl_str_mv | 2023-08-17T17:03:52Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | nitrofuranyl amides mycobacterium tuberculosis spontaneous mutagenesis whole-genome sequencing |
| datacite.titles.title.fl_str_mv | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| dc.contributor.none.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Mokrousov, Igor Slavchev, Ivaylo Solovieva, Natalia Dogonadze, Marine Vyazovaya, Anna Valcheva, Violeta Masharsky, Aleksey Belopolskaya, Olesya Dimitrov, Simeon Zhuravlev, Viacheslav Portugal, Isabel Perdigão, João Dobrikov, Georgi M. |
| dc.date.Accepted.fl_str_mv | 2022-09-12T00:00:00Z |
| dc.date.available.fl_str_mv | 2023-08-17T17:03:52Z |
| dc.date.embargoed.fl_str_mv | 2023-08-17T17:03:52Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10451/58917 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | MDPI |
| dc.rights.cclincense.fl_str_mv | http://creativecommons.org/licenses/by/4.0/ |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | nitrofuranyl amides mycobacterium tuberculosis spontaneous mutagenesis whole-genome sequencing |
| dc.title.fl_str_mv | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | We performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 was used for in vitro selection of spontaneous resistant mutants. The same mutations in six genes were detected in bacterial cultures grown under increased concentrations of 11 (2×, 4×, 8× MIC). The mutant positions were presented as mixed wild type and mutant alleles while increasing the concentration of the compound led to the semi-proportional and significant increase in mutant alleles. The identified genes belong to different categories and pathways. Some of them were previously reported as mediating drug resistance or drug tolerance, and counteracting oxidative and nitrosative stress, in particular: Rv0224c, fbiC, iniA, and Rv1592c. Gene-set interaction analysis revealed a certain weak interaction for gene pairs Rv1592–Rv1639c and Rv1592–Rv0224c. To conclude, this study experimentally demonstrated a multifaceted primary genetic response of M. tuberculosis to the action of nitrofurans. All three 11-treated subcultures independently presented the same six SNPs, which suggests their non-random occurrence and likely causative relationship between compound action and possible resistance mechanism. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/0b731d5c-6c93-4f93-bbd2-cd1383bd8ad7/download |
| funding.funder.alternateName_str_mv | FCT FCT |
| funding.funder.identifier_str_mv | http://doi.org/10.13039/501100001871 http://doi.org/10.13039/501100001871 |
| funding.funder.name_str_mv | Fundação para a Ciência e a Tecnologia Fundação para a Ciência e a Tecnologia |
| funding.name_str_mv | 6817 - DCRRNI ID CEEC IND 2017 |
| id | ul_35e5c28414d4aa2700a439ad2a7e4fc2 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10451/58917 |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
| network_acronym_str | ul |
| network_name_str | Repositório da Universidade de Lisboa |
| oai_identifier_str | oai:repositorio.ulisboa.pt:10451/58917 |
| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Mokrousov, Igor Mokrousov, Igor http://orcid.org/0000-0001-5924-0576 0000-0001-5924-0576 Slavchev, Ivaylo Solovieva, Natalia Dogonadze, Marine Vyazovaya, Anna Valcheva, Violeta Masharsky, Aleksey Belopolskaya, Olesya Belopolskaya, Olesya http://orcid.org/0000-0003-2002-4192 0000-0003-2002-4192 Dimitrov, Simeon Zhuravlev, Viacheslav Zhuravlev, Viacheslav http://orcid.org/0000-0001-6906-6225 0000-0001-6906-6225 Portugal, Isabel Portugal, Isabel https://www.ciencia-id.pt/E310-5746-C205 E310-5746-C205 http://orcid.org/0000-0002-7843-0006 0000-0002-7843-0006 Perdigão, João Perdigão, João https://www.ciencia-id.pt/991C-F26A-9843 991C-F26A-9843 http://orcid.org/0000-0002-0339-1305 0000-0002-0339-1305 Dobrikov, Georgi M. |
| publishDate | 2022 |
| publisher.none.fl_str_mv | MDPI |
| reponame_str | Repositório da Universidade de Lisboa |
| repository_id_str | urn:repositoryAcronym:ul |
| service_str_mv | urn:repositoryAcronym:ul |
| spelling | engMDPIpt_PTWe performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 was used for in vitro selection of spontaneous resistant mutants. The same mutations in six genes were detected in bacterial cultures grown under increased concentrations of 11 (2×, 4×, 8× MIC). The mutant positions were presented as mixed wild type and mutant alleles while increasing the concentration of the compound led to the semi-proportional and significant increase in mutant alleles. The identified genes belong to different categories and pathways. Some of them were previously reported as mediating drug resistance or drug tolerance, and counteracting oxidative and nitrosative stress, in particular: Rv0224c, fbiC, iniA, and Rv1592c. Gene-set interaction analysis revealed a certain weak interaction for gene pairs Rv1592–Rv1639c and Rv1592–Rv0224c. To conclude, this study experimentally demonstrated a multifaceted primary genetic response of M. tuberculosis to the action of nitrofurans. All three 11-treated subcultures independently presented the same six SNPs, which suggests their non-random occurrence and likely causative relationship between compound action and possible resistance mechanism.application/pdfpt_PTMolecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous MutantsPersonalMokrousov, IgorDSpacehttp://dspace.org/items/0ab00fcb-3049-4e7e-b995-8e45b21c43e4DSpacehttp://dspace.org/items/0ab00fcb-3049-4e7e-b995-8e45b21c43e4MokrousovIgorORCIDhttp://orcid.org0000-0001-5924-0576Researcher IDhttps://www.researcherid.comJ-3640-2014Scopus Author IDhttps://www.scopus.com7003916739Slavchev, IvayloSolovieva, NataliaDogonadze, MarineVyazovaya, AnnaValcheva, VioletaMasharsky, AlekseyPersonalBelopolskaya, OlesyaDSpacehttp://dspace.org/items/dac967ad-f99e-4ba9-8962-5adae8765bbfDSpacehttp://dspace.org/items/dac967ad-f99e-4ba9-8962-5adae8765bbfBelopolskayaOlesyaORCIDhttp://orcid.org0000-0003-2002-4192Researcher IDhttps://www.researcherid.comG-9066-2017Scopus Author IDhttps://www.scopus.com55250034500Dimitrov, SimeonPersonalZhuravlev, ViacheslavDSpacehttp://dspace.org/items/0660b61c-4a04-4548-afc3-b84e5e5a1882DSpacehttp://dspace.org/items/0660b61c-4a04-4548-afc3-b84e5e5a1882ZhuravlevViacheslavORCIDhttp://orcid.org0000-0001-6906-6225Researcher IDhttps://www.researcherid.comH-1223-2017Scopus Author IDhttps://www.scopus.com57204401142PersonalPortugal, IsabelDSpacehttp://dspace.org/items/4484da69-843c-4a20-af02-b3c111f84324DSpacehttp://dspace.org/items/4484da69-843c-4a20-af02-b3c111f84324PortugalIsabelCiência IDhttps://www.ciencia-id.ptE310-5746-C205ORCIDhttp://orcid.org0000-0002-7843-0006PersonalPerdigão, JoãoDSpacehttp://dspace.org/items/26de40fc-fc1d-4ff9-a242-3bb398e3ac1eDSpacehttp://dspace.org/items/26de40fc-fc1d-4ff9-a242-3bb398e3ac1eLucas Mota PerdigãoJoão RubenCiência IDhttps://www.ciencia-id.pt991C-F26A-9843ORCIDhttp://orcid.org0000-0002-0339-1305Scopus Author IDhttps://www.scopus.com24723211800Dobrikov, Georgi M.HostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@reitoria.ulisboa.ptrepositorio@reitoria.ulisboa.ptISSNIsPartOf1424-8247DOIIsPartOf10.3390/ph150911362023-08-17T17:03:52Z2022-09-122023-01-02T16:43:56Z2022-09-12T00:00:00ZHandlehttp://hdl.handle.net/10451/58917http://purl.org/coar/access_right/c_abf2open accessnitrofuranyl amidesmycobacterium tuberculosisspontaneous mutagenesiswhole-genome sequencing2535951 bytesFundação para a Ciência e a TecnologiaResearch Institute for Medicines6817 - DCRRNI IDCrossref Funder IDhttp://doi.org/10.13039/501100001871Fundação para a Ciência e a TecnologiaNot AvailableCEEC IND 2017Crossref Funder IDhttp://doi.org/10.13039/501100001871literaturehttp://purl.org/coar/resource_type/c_6501journal article2022-09-12http://creativecommons.org/licenses/by/4.0/http://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/0b731d5c-6c93-4f93-bbd2-cd1383bd8ad7/downloadPharmaceuticals1591136 |
| spellingShingle | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants Mokrousov, Igor nitrofuranyl amides mycobacterium tuberculosis spontaneous mutagenesis whole-genome sequencing |
| status | SINGLETON |
| subject.fl_str_mv | nitrofuranyl amides mycobacterium tuberculosis spontaneous mutagenesis whole-genome sequencing |
| title | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| title_full | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| title_fullStr | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| title_full_unstemmed | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| title_short | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| title_sort | Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants |
| topic | nitrofuranyl amides mycobacterium tuberculosis spontaneous mutagenesis whole-genome sequencing |
| topic_facet | nitrofuranyl amides mycobacterium tuberculosis spontaneous mutagenesis whole-genome sequencing |
| url | http://hdl.handle.net/10451/58917 |
| visible | 1 |