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      Mutations in the anti-sigma H factor RshA confer resistance to econazole and clotrimazole in Mycobacterium smegmatis

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          Abstract

          Azole drugs such as econazole, are active on Mycobacterium tuberculosis and Mycobacterium smegmatis ; however, the identification of their target(s) is still pending. It has been reported that mutations in the non-essential system mmpL5- mmpS5 conferred resistance to econazole in M. tuberculosis . We herein report that an azole-resistant mutant screen in M. smegmatis rendered mutations in rshA, encoding a non-essential anti-sigma H protein.

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          Comprehensive Essentiality Analysis of the Mycobacterium tuberculosis Genome via Saturating Transposon Mutagenesis

          Michael A. DeJesus, Elias R. Gerrick, Weizhen Xu … (2017)
          ABSTRACT   For decades, identifying the regions of a bacterial chromosome that are necessary for viability has relied on mapping integration sites in libraries of random transposon mutants to find loci that are unable to sustain insertion. To date, these studies have analyzed subsaturated libraries, necessitating the application of statistical methods to estimate the likelihood that a gap in transposon coverage is the result of biological selection and not the stochasticity of insertion. As a result, the essentiality of many genomic features, particularly small ones, could not be reliably assessed. We sought to overcome this limitation by creating a completely saturated transposon library in Mycobacterium tuberculosis. In assessing the composition of this highly saturated library by deep sequencing, we discovered that a previously unknown sequence bias of the Himar1 element rendered approximately 9% of potential TA dinucleotide insertion sites less permissible for insertion. We used a hidden Markov model of essentiality that accounted for this unanticipated bias, allowing us to confidently evaluate the essentiality of features that contained as few as 2 TA sites, including open reading frames (ORF), experimentally identified noncoding RNAs, methylation sites, and promoters. In addition, several essential regions that did not correspond to known features were identified, suggesting uncharacterized functions that are necessary for growth. This work provides an authoritative catalog of essential regions of the M. tuberculosis genome and a statistical framework for applying saturating mutagenesis to other bacteria.
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            Variation among genome sequences of H37Rv strains of Mycobacterium tuberculosis from multiple laboratories.

            Thomas Ioerger, Yicheng Feng, Krishna Ganesula … (2010)
            The publication of the complete genome sequence for Mycobacterium tuberculosis H37Rv in 1998 has had a great impact on the research community. Nonetheless, it is suspected that genetic differences have arisen in stocks of H37Rv that are maintained in different laboratories. In order to assess the consistency of the genome sequences among H37Rv strains in use and the extent to which they have diverged from the original strain sequenced, we carried out whole-genome sequencing on six strains of H37Rv from different laboratories. Polymorphisms at 73 sites were observed, which were shared among the lab strains, though 72 of these were also shared with H37Ra and are likely to be due to sequencing errors in the original H37Rv reference sequence. An updated H37Rv genome sequence should be valuable to the tuberculosis research community as well as the broader microbial research community. In addition, several polymorphisms unique to individual strains and several shared polymorphisms were identified and shown to be consistent with the known provenance of these strains. Aside from nucleotide substitutions and insertion/deletions, multiple IS6110 transposition events were observed, supporting the theory that they play a significant role in plasticity of the M. tuberculosis genome. This genome-wide catalog of genetic differences can help explain any phenotypic differences that might be found, including a frameshift mutation in the mycocerosic acid synthase gene which causes two of the strains to be deficient in biosynthesis of the surface glycolipid phthiocerol dimycocerosate (PDIM). The resequencing of these six lab strains represents a fortuitous "in vitro evolution" experiment that demonstrates how the M. tuberculosis genome continues to evolve even in a controlled environment.
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              Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system.

              Anna Milano, Maria Pasca, Roberta Provvedi … (2009)
              Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. Moreover, the recent isolation of M. tuberculosis strains resistant to both first- and second-line antitubercular drugs (XDR-TB) threatens to make the treatment of this disease extremely difficult and becoming a threat to public health worldwide. Recently, it has been shown that azoles are potent inhibitors of mycobacterial cell growth and have antitubercular activity in mice, thus favoring the hypothesis that these drugs may constitute a novel strategy against tuberculosis disease. To investigate the mechanisms of resistance to azoles in mycobacteria, we isolated and characterized several spontaneous azoles resistant mutants from M. tuberculosis and Mycobacterium bovis BCG. All the analyzed resistant mutants exhibited both increased econazole efflux and increased transcription of mmpS5-mmpL5 genes, encoding a hypothetical efflux system belonging to the resistance-nodulation-division (RND) family of transporters. We found that the up-regulation of mmpS5-mmpL5 genes was linked to mutations either in the Rv0678 gene, hypothesized to be involved in the transcriptional regulation of this efflux system, or in its putative promoter/operator region.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Access Microbiol
                Journal ID (iso-abbrev): Access Microbiol
                Journal ID (hwp): acmi
                Journal ID (publisher-id): acmi
                Title: Access Microbiology
                Publisher: Microbiology Society
                ISSN (Electronic): 2516-8290
                Publication date Collection: 2019
                Publication date (Electronic): 29 October 2019
                Publication date PMC-release: 29 October 2019
                Volume: 1
                Issue: 10
                Electronic Location Identifier: e000070
                Affiliations
                [ 1​ ] departmentLaboratorio de Microbiología Molecular , Facultad de Ciencias Médicas, Universidad Nacional de Rosario , Rosario, Argentina
                [ 2​ ] departmentDepartment of Computer Science and Engineering , Texas A&M University , College Station, TX, USA
                [ 3​ ] departmentTB Discovery Research , Infectious Disease Research Institute , Seattle, WA, USA
                [ †​ ]Present address: Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina
                Author notes
                *Correspondence: Héctor R. Morbidoni, morbiatny@ 123456yahoo.com
                *Correspondence: Tanya Parish, Tanya.Parish@ 123456idri.org
                Author information
                https://orcid.org/0000-0003-4180-9677
                https://orcid.org/0000-0002-8982-3489
                https://orcid.org/0000-0001-7507-0423
                Article
                Publisher ID: 000070
                DOI: 10.1099/acmi.0.000070
                PMC ID: 7491931
                SO-VID: 67ae6349-a839-4085-a2ec-725514b08038
                Copyright © © 2019 The Authors
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License.

                History
                Date received : 18 April 2019
                Date accepted : 02 October 2019
                Funding
                Funded by: Agencia Nacional de Promoción Científica y Tecnológica
                Award ID: ANPCyT PICT 1063
                Award Recipient : HECTOR RICARDO MORBIDONI
                Categories
                Subject: Short Communication
                Custom metadata
                OpenAccessEmbargo 0

                Keywords: mycobacterium smegmatis,mycobacterium tuberculosis,econazole,rsha
                Data availability:
                Keywords: mycobacterium smegmatis, mycobacterium tuberculosis, econazole, rsha

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