Rv1255c, a dormancy-related transcriptional regulator of TetR family in Mycobacterium tuberculosis, enhances isoniazid tolerance in Mycobacterium smegmatis.
Journal
The Journal of antibiotics
ISSN: 1881-1469
Titre abrégé: J Antibiot (Tokyo)
Pays: England
ID NLM: 0151115
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
received:
16
02
2023
accepted:
12
09
2023
revised:
29
08
2023
medline:
28
11
2023
pubmed:
12
10
2023
entrez:
11
10
2023
Statut:
ppublish
Résumé
Mycobacterium tuberculosis is exposed to diverse stresses inside the host during dormancy. Meanwhile, many metabolic and transcriptional regulatory changes occur, resulting in physiological modifications that help M. tuberculosis to adapt to these stresses. The same physiological changes also cause antibiotic tolerance in dormant M. tuberculosis. However, the transcriptional regulatory mechanism of antibiotic tolerance during dormancy remains unclear. Here, we showed that the expression of Rv1255c, an uncharacterised member of the tetracycline repressor family of transcriptional regulators, is upregulated during different stresses and hypoxia-induced dormancy. Antibiotic tolerance and efflux activities of Mycobacterium smegmatis constitutively expressing Rv1255c were analysed, and interestingly, it showed increased isoniazid tolerance and efflux activity. The intrabacterial isoniazid concentrations were found to be low in M. smegmatis expressing Rv1255c. Moreover, orthologs of the M. tuberculosis katG, gene of the enzyme which activates the first-line prodrug isoniazid, are overexpressed in this strain. Structural analysis of isoforms of KatG enzymes in M. smegmatis identified major amino acid substitutions associated with isoniazid resistance. Thus, we showed that Rv1255c helps M. smegmatis tolerate isoniazid by orchestrating drug efflux machinery. In addition, we showed that Rv1255c also causes overexpression of katG isoform in M. smegmatis which has amino acid substitutions as found in isoniazid-resistant katG in M. tuberculosis.
Identifiants
pubmed: 37821540
doi: 10.1038/s41429-023-00661-8
pii: 10.1038/s41429-023-00661-8
doi:
Substances chimiques
Anti-Bacterial Agents
0
Antitubercular Agents
0
Bacterial Proteins
0
Catalase
EC 1.11.1.6
Isoniazid
V83O1VOZ8L
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
720-727Informations de copyright
© 2023. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.
Références
Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am. 1993;77:1205–17.
doi: 10.1016/S0025-7125(16)30188-2
pubmed: 8231408
WHO. Global Tuberculosis Report 2020 – World. ReliefWeb. 2020;1–232.
World Health Organization. Global Tuberculosis Report 2021. Geneva: ©World Health Organization; 2021. p 57.
Gengenbacher M, Kaufmann SHE. Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev. 2012;36:514–32.
doi: 10.1111/j.1574-6976.2012.00331.x
pubmed: 22320122
Trutneva KA, Shleeva MO, Demina GR, Vostroknutova GN, Kaprelyans AS. One-year old dormant, “non-culturable” Mycobacterium tuberculosis preserves significantly diverse protein profile. Front Cell Infect Microbiol. 2020;10:26.
doi: 10.3389/fcimb.2020.00026
pubmed: 32117801
pmcid: 7025520
Wayne LG, Sohaskey CD. Nonreplicating persistence of Mycobacterium tuberculosis. Annu Rev Microbiol. 2001;55:139–63.
doi: 10.1146/annurev.micro.55.1.139
pubmed: 11544352
Gopinath V, Raghunandanan S, Gomez RL, Jose L, Surendran A, Ramachandran R, et al. Profiling the proteome of Mycobacterium tuberculosis during dormancy and reactivation. Mol Cell Proteom. 2015;14:2160–76.
doi: 10.1074/mcp.M115.051151
Wayne LG, Hayes LG. An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun. 1996;64:2062–9.
doi: 10.1128/iai.64.6.2062-2069.1996
pubmed: 8675308
pmcid: 174037
Ojha AK, Baughn AD, Sambandan D, Hsu T, Trivelli X, Guerardel Y, et al. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol. 2008;69:164–74.
doi: 10.1111/j.1365-2958.2008.06274.x
pubmed: 18466296
pmcid: 2615189
Flentie K, Harrison GA, Tükenmez H, Livny J, Good JAD, Sarkar S, et al. Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 2019;116:10510–7.
doi: 10.1073/pnas.1818009116
pubmed: 31061116
pmcid: 6535022
Voskuil MI, Bartek IL, Visconti K, Schoolnik GK. The response of Mycobacterium tuberculosis to reactive oxygen and nitrogen species. Front Microbiol. 2011;2:105.
doi: 10.3389/fmicb.2011.00105
pubmed: 21734908
pmcid: 3119406
Deb C, Lee C-M, Dubey VS, Daniel J, Abomoelak B, Sirakova TD, et al. A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen. PLoS One. 2009;4:e6077.
doi: 10.1371/journal.pone.0006077
pubmed: 19562030
pmcid: 2698117
Shastri MD, Shukla SD, Chong WC, Dua K, Peterson GM, Patel RP, et al. Role of oxidative stress in the pathology and management of human tuberculosis. Oxid Med Cell Longev. 2018;2018:7695364.
Li G, Zhang J, Guo Q, Jiang Y, Wei J, Zhao LL, et al. Efflux pump gene expression in multidrug-resistant Mycobacterium tuberculosis clinical isolates. PLoS One. 2015;10:e0119013.
doi: 10.1371/journal.pone.0119013
pubmed: 25695504
pmcid: 4335044
Bhandol H, Alindogan J, De Guzman A, Lim R. Review: Structure and transcriptional regulation of the Acr efflux pumps and their role in antibiotic resistance in Escherichia coli. Undergrad J Exp Microbiol Immunol. 2020;6:1–16.
Liu J, Shi W, Zhang S, Hao X, Maslov DA, Shur KV, et al. Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide, isoniazid, and streptomycin in M. tuberculosis. Front Microbiol. 2019;10:216.
doi: 10.3389/fmicb.2019.00216
pubmed: 30837962
pmcid: 6389670
Liu H, Yang M, He Z-G. Novel TetR family transcriptional factor regulates expression of multiple transport-related genes and affects rifampicin resistance in Mycobacterium smegmatis. Sci Rep. 2016;6:27489.
doi: 10.1038/srep27489
pubmed: 27271013
pmcid: 4895335
Remm S, Earp JC, Dick T, Dartois V, Seeger MA. Critical discussion on drug efflux in Mycobacterium tuberculosis. FEMS Microbiol Rev. 2022;46:fuab050.
Balhana RJC, Singla A, Sikder MH, Withers M, Kendall SL. Global analyses of TetR family transcriptional regulators in mycobacteria indicates conservation across species and diversity in regulated functions. BMC Genomics. 2015;16:1–12.
doi: 10.1186/s12864-015-1696-9
Luo L, Zhu L, Yue J, Liu J, Liu G, Zhang X, et al. Antigens Rv0310c and Rv1255c are promising novel biomarkers for the diagnosis of Mycobacterium tuberculosis infection. Emerg Microbes Infect. 2017;6:1–8.
doi: 10.1038/emi.2017.54
Rustad TR, Harrell MI, Liao R, Sherman DR. The enduring hypoxic response of Mycobacterium tuberculosis. PLoS One. 2008;3:e1502.
doi: 10.1371/journal.pone.0001502
pubmed: 18231589
pmcid: 2198943
Sun X, Zhang L, Jiang J, Ng M, Cui Z, Mai J, et al. Transcription factors Rv0081 and Rv3334 connect the early and the enduring hypoxic response of Mycobacterium tuberculosis. Virulence. 2018;9:1468.
doi: 10.1080/21505594.2018.1514237
pubmed: 30165798
pmcid: 6177252
Galagan JE, Minch K, Peterson M, Lyubetskaya A, Azizi E, Sweet L, et al. The Mycobacterium tuberculosis regulatory network and hypoxia. Nature. 2013;499:178–83.
doi: 10.1038/nature12337
pubmed: 23823726
pmcid: 4087036
Martin A, Camacho M, Portaels F, Palomino JC. Resazurin microtiter assay plate testing of Mycobacterium tuberculosis susceptibilities to second-line drugs: rapid, simple, and inexpensive method. Antimicrob Agents Chemother. 2003;47:3616.
doi: 10.1128/AAC.47.11.3616-3619.2003
pubmed: 14576129
pmcid: 253784
Pal S, Misra A, Banerjee S, Dam B. Adaptation of ethidium bromide fluorescence assay to monitor activity of efflux pumps in bacterial pure cultures or mixed population from environmental samples. J King Saud Univ Sci. 2020;32:939–45.
doi: 10.1016/j.jksus.2019.06.002
Valdivia RH, Hromockyj AE, Monack D, Ramakrishnan L, Falkow S. Applications for green fluorescent protein (GFP) in the study of host-pathogen interactions. Gene. 1996;173:47–52.
Jose L, Ramachandran R, Bhagavat R, Gomez RL, Chandran A, Raghunandanan S, et al. Hypothetical protein Rv3423.1 of Mycobacterium tuberculosis is a histone acetyltransferase. FEBS J. 2016;283:265–81.
doi: 10.1111/febs.13566
pubmed: 26476134
Meng EC, Pettersen EF, Couch GS, Huang CC, Ferrin TE. Tools for integrated sequence-structure analysis with UCSF Chimera. BMC Bioinforma. 2006;7:1–10.
doi: 10.1186/1471-2105-7-339
Engohang-Ndong J, Baillat D, Aumercier M, Bellefontaine F, Besra GS, Locht C, et al. EthR, a repressor of the TetR/CamR family implicated in ethionamide resistance in mycobacteria, octamerizes cooperatively on its operator. Mol Microbiol. 2004;51:175–88.
doi: 10.1046/j.1365-2958.2003.03809.x
pubmed: 14651620
Ramos JL, Martínez-Bueno M, Molina-Henares AJ, Terán W, Watanabe K, Zhang X, et al. The TetR family of transcriptional repressors. Microbiol Mol Biol Rev. 2005;69:326–56.
doi: 10.1128/MMBR.69.2.326-356.2005
pubmed: 15944459
pmcid: 1197418
Bollela VR, Namburete EI, Feliciano CS, Macheque D, Harrison LH, Caminero JA. Detection of katG and inhA mutations to guide isoniazid and ethionamide use for drug-resistant tuberculosis. Int J Tuberc Lung Dis. 2016;20:1099.
doi: 10.5588/ijtld.15.0864
pubmed: 27393546
Ai JW, Ruan QL, Liu QH, Zhang WH. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerg Microbes Infect. 2016;5:e10.
doi: 10.1038/emi.2016.10
pubmed: 26839146
pmcid: 4777925
Gomez RL, Jose L, Ramachandran R, Raghunandanan S, Muralikrishnan B, Johnson JB, et al. The multiple stress responsive transcriptional regulator Rv3334 of Mycobacterium tuberculosis is an autorepressor and a positive regulator of kstR. FEBS J. 2016;283:3056–71.
doi: 10.1111/febs.13791
pubmed: 27334653
Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tube Lung Dis. 1998;79:3–29.
doi: 10.1054/tuld.1998.0002
Gao CH, Wei WP, Tao HL, Cai LK, Jia WZ, Hu L, et al. Cross-talk between the three furA orthologs in Mycobacterium smegmatis and the contribution to isoniazid resistance. J Biochem. 2019;166:237–43.
doi: 10.1093/jb/mvz030
pubmed: 30993320
Barozi V, Musyoka TM, Sheik Amamuddy O, Tastan Bishop Ö. Deciphering isoniazid drug resistance mechanisms on dimeric Mycobacterium tuberculosis KatG via post-molecular dynamics analyses including combined dynamic residue network metrics. ACS Omega. 2022;7:13313–32.
doi: 10.1021/acsomega.2c01036
pubmed: 35474779
pmcid: 9025985