Deciphering the possible role of MmpL7 efflux pump in SQ109 resistance in Mycobacterium tuberculosis.

Mycobacterium tuberculosis / drug effects Microbial Sensitivity Tests Humans Antitubercular Agents / pharmacology Membrane Transport Proteins / genetics Bacterial Proteins / genetics Tuberculosis, Multidrug-Resistant / microbiology Drug Resistance, Multiple, Bacterial / genetics Adamantane / pharmacology Mutation Mycobacterium smegmatis / genetics Ethylenediamines
Mycobacterium tuberculosis MmpL7 SQ109 Susceptibility

Journal

Annals of clinical microbiology and antimicrobials
ISSN: 1476-0711
Titre abrégé: Ann Clin Microbiol Antimicrob
Pays: England
ID NLM: 101152152

Informations de publication

Date de publication:
28 Sep 2024
Historique:
received: 27 03 2024
accepted: 20 09 2024
medline: 29 9 2024
pubmed: 29 9 2024
entrez: 28 9 2024
Statut: epublish

Résumé

SQ109 is a promising candidate drug for the treatment of patients with drug-resistant tuberculosis (DR-TB). The purpose of this study was to investigate the activity of SQ109 against clinical isolates of Mycobacterium tuberculosis (MTB) from patients with multidrug-resistant TB (MDR-TB) and pre-extensively drug-resistant TB (pre-XDR-TB), and to explore new drug-resistant mechanisms of SQ109. We evaluated the in vitro activity of SQ109 against clinical isolates from patients with MDR-TB and pre-XDR-TB using minimal inhibitory concentration (MIC) assay. The drug-resistant gene, mmpL3 of SQ109-resistant strains was sequenced, and a quantitative real-time PCR assay was used to analyze 28 efflux pump genes in SQ109-resistant strains without mmpL3 mutations. The role of candidate efflux pumps mmpL5 and mmpL7 on the MIC of SQ109 was evaluated using recombinantly cloned MmpL5 and MmpL7 expressed in Mycobacterium smegmatis. The MIC Our data demonstrated that SQ109 exhibited excellent levels of in vitro activity against MTB. MmpL7 may be a potential gene for MTB resistance to SQ109, providing a useful target for detecting SQ109 resistance in MTB.

Sections du résumé

BACKGROUND BACKGROUND
SQ109 is a promising candidate drug for the treatment of patients with drug-resistant tuberculosis (DR-TB). The purpose of this study was to investigate the activity of SQ109 against clinical isolates of Mycobacterium tuberculosis (MTB) from patients with multidrug-resistant TB (MDR-TB) and pre-extensively drug-resistant TB (pre-XDR-TB), and to explore new drug-resistant mechanisms of SQ109.
METHODS METHODS
We evaluated the in vitro activity of SQ109 against clinical isolates from patients with MDR-TB and pre-XDR-TB using minimal inhibitory concentration (MIC) assay. The drug-resistant gene, mmpL3 of SQ109-resistant strains was sequenced, and a quantitative real-time PCR assay was used to analyze 28 efflux pump genes in SQ109-resistant strains without mmpL3 mutations. The role of candidate efflux pumps mmpL5 and mmpL7 on the MIC of SQ109 was evaluated using recombinantly cloned MmpL5 and MmpL7 expressed in Mycobacterium smegmatis.
RESULTS RESULTS
The MIC
CONCLUSIONS CONCLUSIONS
Our data demonstrated that SQ109 exhibited excellent levels of in vitro activity against MTB. MmpL7 may be a potential gene for MTB resistance to SQ109, providing a useful target for detecting SQ109 resistance in MTB.

Identifiants

DOI: 10.1186/s12941-024-00746-8 PMID: 39342331
pubmed: 39342331
doi: 10.1186/s12941-024-00746-8
pii: 10.1186/s12941-024-00746-8
doi:

Substances chimiques

Antitubercular Agents 0
Membrane Transport Proteins 0
Bacterial Proteins 0
N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine 0
Adamantane PJY633525U
Ethylenediamines 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

87

Subventions

Organisme : Beijing Natural Science Foundation (Youth Program)
ID : No.7224324
Organisme : "Young talents" program of Beijing hospitals Authority
ID : QML20231606

Informations de copyright

© 2024. The Author(s).

Références

World Health Organization. Global tuberculosis report 2023: Geneva: World Health Organization 2023. https://www.who.int/publications/i/item/9789240083851
WHO. World Health Organization WHO Announces Updated Definitions of Extensively Drug-Resistant Tuberculosis. 2021. https://www.who.int/news/item/27-01-2021-who-announces-updated-definitions-of-extensively-drug-resistant-tuberculosis
Zhang MW, Zhou L, Zhang Y, et al. Treatment outcomes of patients with multidrug and extensively drug-resistant tuberculosis in Zhejiang, China. Eur J Med Res. 2021;26:31.
doi: 10.1186/s40001-021-00502-0 pubmed: 33812390 pmcid: 8019161
Black TA, Buchwald UK. The pipeline of new molecules and regimens against drug-resistant tuberculosis. J Clin Tuberc Other Mycobact Dis. 2021;25:100285.
doi: 10.1016/j.jctube.2021.100285 pubmed: 34816020 pmcid: 8593651
Vanino E, Granozzi B, Akkerman OW, et al. Update of drug-resistant tuberculosis treatment guidelines: a turning point. Int J Infect Dis. 2023;130(Suppl 1):S12–5.
doi: 10.1016/j.ijid.2023.03.013 pubmed: 36918080
Tahlan K, Wilson R, Kastrinsky DB, et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012;56:1797–809.
doi: 10.1128/AAC.05708-11 pubmed: 22252828 pmcid: 3318387
Chen P, Gearhart J, Protopopova M, et al. Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro. J Antimicrob Chemother. 2006;58:332–7.
doi: 10.1093/jac/dkl227 pubmed: 16751637
Reddy VM, Einck L, Andries K, Nacy CA. Interactions between New Antitubercular drug candidates SQ109 and TMC207. Antimicrob Agents Ch. 2010;54:2840–6.
doi: 10.1128/AAC.01601-09
Zhang ZJ, Pang Y, Wang YF, et al. Differences in risk factors and drug susceptibility between and lung diseases in China. Int J Antimicrob Ag. 2015;45:491–5.
doi: 10.1016/j.ijantimicag.2015.01.012
van Klingeren B, Dessens-Kroon M, van der Laan T, et al. Drug susceptibility testing of complex by use of a high-throughput, reproducible, absolute concentration method. J Clin Microbiol. 2007;45:2662–8.
doi: 10.1128/JCM.00244-07 pubmed: 17537932 pmcid: 1951260
Zhang FZ, Li SS, Wen SA, et al. Comparison of in vitro susceptibility of Mycobacteria against PA-824 to identify key residues of Ddn, the Deazoflavin-Dependent Nitroreductase from. Infect Drug Resist. 2020;13:815–22.
doi: 10.2147/IDR.S240716 pubmed: 32210596 pmcid: 7073430
Pang Y, Zhou Y, Wang SF, et al. A novel method based on high resolution melting (HRM) analysis for MIRU-VNTR genotyping of. J Microbiol Meth. 2011;86:291–7.
doi: 10.1016/j.mimet.2011.05.016
Franzén O, Arner E, Ferella M et al. The short non-coding transcriptome of the Protozoan parasite. Plos Negl Trop D 2011;5.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402–8.
doi: 10.1006/meth.2001.1262 pubmed: 11846609
Lee RE, Protopopova M, Crooks E, et al. Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. J Comb Chem. 2003;5:172–87.
doi: 10.1021/cc020071p pubmed: 12625709
Protopopova M, Hanrahan C, Nikonenko B, et al. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemoth. 2005;56:968–74.
doi: 10.1093/jac/dki319
Sacksteder KA, Protopopova M, Barry CE, et al. Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. Future Microbiol. 2012;7:823–37.
doi: 10.2217/fmb.12.56 pubmed: 22827305
Imran M, Arora MK, Chaudhary A, et al. MmpL3 inhibition as a Promising Approach to develop Novel therapies against Tuberculosis: a spotlight on SQ109, Clinical studies, and patents Literature. Biomedicines. 2022;10(11):2793.
doi: 10.3390/biomedicines10112793 pubmed: 36359313 pmcid: 9687596
Jia J, Tomaszewski JE, Hanrahan C, et al. Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug. Brit J Pharmacol. 2005;144:80–7.
doi: 10.1038/sj.bjp.0705984
Borisov S, Bogorodskaya E, Volchenkov G, et al. Efficiency and safety of chemotherapy regimen with SQ109 in those suffering from multiple drug resistant tuberculosis. Tuberculosis lung Dis. 2018;96:6–18.
doi: 10.21292/2075-1230-2018-96-3-6-18
Bolla JR. Targeting MmpL3 for anti-tuberculosis drug development. Biochem Soc Trans. 2020;48:1463–72.
doi: 10.1042/BST20190950 pubmed: 32662825 pmcid: 7458404
Xu J, Li D, Shi J, et al. Bedquiline Resistance mutations: correlations with drug exposures and impact on the Proteome in M. Tuberculosis. Antimicrob Agents Chemother. 2023;67:e0153222.
doi: 10.1128/aac.01532-22 pubmed: 37255473
Pasca MR, Guglierame P, De Rossi E, et al. mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob Agents Ch. 2005;49:4775–7.
doi: 10.1128/AAC.49.11.4775-4777.2005
Camacho LRCP, Raynaud C, Laneelle MA, et al. Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier. J Biol Chem. 2001;276:9.
doi: 10.1074/jbc.M100662200

Auteurs

Wei Jing (W)

Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China.

Fuzhen Zhang (F)

Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China.
Department of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, PR China.

Yuanyuan Shang (Y)

Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China.

Wenhui Shi (W)

Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China.

Cong Yao (C)

Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China.

Xuxia Zhang (X)

Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China.

Naihui Chu (N)

Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China. chunaihui1994@sina.com.

Jie Lu (J)

Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 101149, PR China. lujiebch@163.com.

Jinfeng Yuan (J)

Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, PR China. yuanjinfeng0920@163.com.

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Classifications MeSH

questionsmedicales.fr › Bactéries › Bactéries à Gram positif › Bâtonnets à Gram positif › Bâtonnets asporogènes à Gram positif › Bâtonnets asporogènes réguliers à Gram positif › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité microbienne › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Antituberculeux › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines bactériennes › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Infections bactériennes à Gram positif › Infections à Actinomycetales › Infections à Mycobacterium › Tuberculose › Tuberculose multirésistante › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Multirésistance aux médicaments › Multirésistance bactérienne aux médicaments › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures alicycliques › Adamantane › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Bactéries › Bactéries à Gram positif › Bâtonnets à Gram positif › Bâtonnets asporogènes à Gram positif › Bâtonnets asporogènes réguliers à Gram positif › Mycobacteriaceae › Mycobacterium › Mycobactéries non tuberculeuses › Mycobacterium smegmatis › Deciphering the possible role of MmpL7 efflux...
questionsmedicales.fr › Composés chimiques organiques › Amines › Polyamines › Diamines › Éthylènediamines › Deciphering the possible role of MmpL7 efflux...