Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis.
Tuberculosis is still a leading cause of death worldwide. The selection and spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Recently, two different classes of chemical series, the benzothiazinones (B...
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oai:doaj.org-article:74e771f1a76c425294267f9b2634a6f72021-11-18T07:35:18ZAnalogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis.1932-620310.1371/journal.pone.0026675https://doaj.org/article/74e771f1a76c425294267f9b2634a6f72011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22069462/?tool=EBIhttps://doaj.org/toc/1932-6203Tuberculosis is still a leading cause of death worldwide. The selection and spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Recently, two different classes of chemical series, the benzothiazinones (BTZ) and the dinitrobenzamide (DNB) derivatives have been found to be highly active against M. tuberculosis, including XDR-TB strains. The target of BTZs is DprE1 protein which works in concert with DprE2 to form the heteromeric decaprenylphosphoryl-β-D-ribose 2'-epimerase, involved in Decaprenyl-Phospho-Arabinose (DPA) biosynthesis. Interestingly, it has been shown that the DNBs block the same pathway thus suggesting that both drugs could share the same target. Moreover, in Mycobacterium smegmatis the overexpression of the NfnB nitroreductase led to the inactivation of the BTZs by reduction of a critical nitro-group to an amino-group. In this work several spontaneous M. smegmatis mutants resistant to DNBs were isolated. Sixteen mutants, showing high levels of DNB resistance, exhibited a mutation in the Cys394 of DprE1. Using fluorescence titration and mass spectrometry it has been possible to monitor the binding between DprE1 and DNBs, achieving direct evidence that MSMEG_6382 is the cellular target of DNBs in mycobacteria. Additionally, M. smegmatis mutants having low levels of resistance to DNBs harbor various mutations in MSMEG_6503 gene encoding the transcriptional repressor of the nitroreductase NfnB. By LC/MS analysis it has been demonstrated that NfnB is responsible for DNB inactivation. Taken together, our data demonstrate that both DNB and BTZ drugs share common resistance mechanisms in M. smegmatis.Ana Luisa de Jesus Lopes RibeiroGiulia DegiacomiFanny EwannSilvia BuroniMaria Loreto IncandelaLaurent R ChiarelliGiorgia MoriJaeseung KimMonica Contreras-DominguezYoung-Sam ParkSung-Jun HanPriscille BrodinGiovanna ValentiniMenico RizziGiovanna RiccardiMaria Rosalia PascaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 11, p e26675 (2011) |
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Medicine R Science Q Ana Luisa de Jesus Lopes Ribeiro Giulia Degiacomi Fanny Ewann Silvia Buroni Maria Loreto Incandela Laurent R Chiarelli Giorgia Mori Jaeseung Kim Monica Contreras-Dominguez Young-Sam Park Sung-Jun Han Priscille Brodin Giovanna Valentini Menico Rizzi Giovanna Riccardi Maria Rosalia Pasca Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. |
| description |
Tuberculosis is still a leading cause of death worldwide. The selection and spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Recently, two different classes of chemical series, the benzothiazinones (BTZ) and the dinitrobenzamide (DNB) derivatives have been found to be highly active against M. tuberculosis, including XDR-TB strains. The target of BTZs is DprE1 protein which works in concert with DprE2 to form the heteromeric decaprenylphosphoryl-β-D-ribose 2'-epimerase, involved in Decaprenyl-Phospho-Arabinose (DPA) biosynthesis. Interestingly, it has been shown that the DNBs block the same pathway thus suggesting that both drugs could share the same target. Moreover, in Mycobacterium smegmatis the overexpression of the NfnB nitroreductase led to the inactivation of the BTZs by reduction of a critical nitro-group to an amino-group. In this work several spontaneous M. smegmatis mutants resistant to DNBs were isolated. Sixteen mutants, showing high levels of DNB resistance, exhibited a mutation in the Cys394 of DprE1. Using fluorescence titration and mass spectrometry it has been possible to monitor the binding between DprE1 and DNBs, achieving direct evidence that MSMEG_6382 is the cellular target of DNBs in mycobacteria. Additionally, M. smegmatis mutants having low levels of resistance to DNBs harbor various mutations in MSMEG_6503 gene encoding the transcriptional repressor of the nitroreductase NfnB. By LC/MS analysis it has been demonstrated that NfnB is responsible for DNB inactivation. Taken together, our data demonstrate that both DNB and BTZ drugs share common resistance mechanisms in M. smegmatis. |
| format |
article |
| author |
Ana Luisa de Jesus Lopes Ribeiro Giulia Degiacomi Fanny Ewann Silvia Buroni Maria Loreto Incandela Laurent R Chiarelli Giorgia Mori Jaeseung Kim Monica Contreras-Dominguez Young-Sam Park Sung-Jun Han Priscille Brodin Giovanna Valentini Menico Rizzi Giovanna Riccardi Maria Rosalia Pasca |
| author_facet |
Ana Luisa de Jesus Lopes Ribeiro Giulia Degiacomi Fanny Ewann Silvia Buroni Maria Loreto Incandela Laurent R Chiarelli Giorgia Mori Jaeseung Kim Monica Contreras-Dominguez Young-Sam Park Sung-Jun Han Priscille Brodin Giovanna Valentini Menico Rizzi Giovanna Riccardi Maria Rosalia Pasca |
| author_sort |
Ana Luisa de Jesus Lopes Ribeiro |
| title |
Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. |
| title_short |
Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. |
| title_full |
Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. |
| title_fullStr |
Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. |
| title_full_unstemmed |
Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. |
| title_sort |
analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in mycobacterium smegmatis. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/74e771f1a76c425294267f9b2634a6f7 |
| work_keys_str_mv |
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