Exploring Genomic Patterns to Identify Drug-Resistant TB: A Comprehensive Study of Age, Gender, Lineage, and Outcome
Abstract
Background: Tuberculosis (TB) is a prevalent bacterial infection caused by Mycobacterium tuberculosis (Mtb), primarily affecting the lungs, with rising incidence rates. Drug-resistant TB strains, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) types, pose challenges with poor treatment success rates and increased mortality. Demographic factors and genomic patterns contribute to drug resistance, emphasizing the need for new drugs targeting specific genomic patterns.
Methods: This study analyzes the impact of demographics, treatment outcomes, and genomic mutations on drug-resistant TB using pattern identification techniques and whole-genome sequencing to discover therapeutic targets. This study primarily focused on the identification and analysis of MDR and XDR strains, considering various demographic characteristics and treatment outcomes. A dataset comprising 2,602 observations was utilized, and pattern recognition techniques were employed to identify significant features. Additionally, the study employs the whole-genome sequencing (WGS) pipeline to identify single nucleotide polymorphisms (SNPs) that result in new mutations in drug-resistant Mtb strains.
Results: The findings of the study revealed that XDR and MDR non-XDR TB were the most prevalent types of drug resistance, and they were associated with unfavorable treatment outcomes, including death or treatment failure. Males exhibited a higher susceptibility to both XDR and MDR non-XDR TB compared to females. The age of onset for both types of resistance was approximately 40 years. Among the observed variants in 31 commonly occurring genes,
Conclusion: These findings introduce a novel set of therapeutic targets specific to MDR and XDR Mtb types, which warrant further investigation for potential therapeutic interventions.
Keywords: Tuberculosis; Drug Resistance; Multidrug resistance; Demographics; Dataset; Gene; Mutations
Full Text:
PDFReferences
Natarajan A, Beena PM, Devnikar AV, Mali S. A systemic review on tuberculosis. Indian Journal of Tuberculosis, (2020); 67(3): 295-311.
Bagcchi S. WHO's global tuberculosis report 2022. The Lancet Microbe, (2023); 4(1):e20.
Gill A, Ugalde I, Febres-Aldana CA, Tuda C. Fluoroquinolone resistant tuberculosis: A case report and literature review. Respiratory Medicine Case Reports, (2019);27:100829.
Phyu AN, Aung ST, Palittapongarnpim P, Htet KK, Mahasirimongkol S, Aung HL, Chaiprasert A, Chongsuvivatwong V. Distribution of Mycobacterium tuberculosis Lineages and Drug Resistance in Upper Myanmar. Tropical Medicine and Infectious Disease, (2022); 7(12):448.
Gabrielsson J, Meibohm B, Weiner D. Pattern recognition in pharmacokinetic data analysis. Journal of the American Association of Pharmaceutical Scientists (2016); 18:47-63.
Cervantes J, Yokobori N, Hong BY. Genetic identification and drug-resistance characterization of Mycobacterium tuberculosis using a portable sequencing device. A pilot study. Antibiotics, (2020); 9(9):548.
Hunt M, Mather AE, Sánchez-Busó L, Page AJ, Parkhill J, et al. ARIBA: rapid antimicrobial resistance genotyping directly from sequencing reads. Microbial genomics, (2017); 3(10): e000131.
Huang Y, Niu B, Gao Y, Fu L, Li W. CD-HIT Suite: a web server for clustering and comparing biological sequences. Bioinformatics, (2010); 26(5):680-2.
Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nature methods, (2012); 9(4):357-9.
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data Processing Subgroup. The sequence alignment/map format and SAMtools. Bioinformatics, (2009); 25(16):2078-9.
John GS, Brot N, Ruan J, Erdjument-Bromage H, Tempst P, Weissbach H, Nathan C. Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates. Proceedings of the National Academy of Sciences, (2001); 98(17):9901-6.
Lee WL, Gold B, Darby C, Brot N, Jiang X, De Carvalho LP, Wellner D, St. John G, Jacobs Jr WR, Nathan C. Mycobacterium tuberculosis expresses methionine sulphoxide reductases A and B that protect from killing by nitrite and hypochlorite. Molecular microbiology, (2009); 71(3):583-93.
Hiasa H. The Glu-84 of the ParC subunit plays critical roles in both topoisomerase IV− Quinolone and Topoisomerase IV− DNA interactions. Biochemistry, (2002); 41(39):11779-85.
Sheng D, Chen X, Li Y, Wang J, Zhuo L, Li Y. ParC, a new partitioning protein, is necessary for the active form of ParA From Myxococcus pMF1 plasmid. Frontiers in Microbiology, (2021); 11(1):623699.
McCann JR, McDonough JA, Pavelka MS, Braunstein M. β-Lactamase can function as a reporter of bacterial protein export during Mycobacterium tuberculosis infection of host cells. Microbiology, (2007); 153(10):3350–9.
Gurvitz A, Hiltunen JK, Kastaniotis AJ. Function of heterologous Mycobacterium tuberculosis InhA, a type 2 fatty acid synthase enzyme involved in extending C20 fatty acids to C60-to-C90 mycolic acids, during de novo lipoic acid synthesis in Saccharomyces cerevisiae. Applied and Environmental Microbiology, (2008); 74(16):5078-85
Schlothauer T, Mogk A, Dougan DA, Bukau B, Turgay K. MecA, an adaptor protein necessary for ClpC chaperone activity. Proceedings of the National Academy of Sciences, (2003); 100(5):2306-11.
Lee YH, Nam KH, Helmann JD. A mutation of the RNA polymerase β′ subunit (rpoC) confers cephalosporin resistance in Bacillus subtilis. Antimicrobial agents and chemotherapy, (2013); 57(1):56-65.
García-Castellanos R, Mallorquí-Fernández G, Marrero A, Potempa J, Coll M, Gomis-Ruth FX. On the transcriptional regulation of methicillin resistance: MecI repressor in complex with its operator. Journal of Biological Chemistry, (2004); 279(17):17888-96.
Blokpoel MC, Murphy HN, O'Toole R, Wiles S, Runn ES, Stewart GR, Young DB, Robertson BD. Tetracycline-inducible gene regulation in mycobacteria. Nucleic acids research, (2005); 33(2): e22-.
He W, Jiang K, Qiu H, Liao L, Wang S. 16-membered ring macrolides and erythromycin induce ermB expression by different mechanisms. BMC microbiology, (2022);
(1):152.
Mérens A, Matrat S, Aubry A, Lascols C, Jarlier V, Soussy CJ, Cavallo JD, Cambau E. The pentapeptide repeat proteins MfpAMt and QnrB4 exhibit opposite effects on DNA gyrase catalytic reactions and on the ternary gyrase-DNA-quinolone complex. Journal of bacteriology, (2009); 191(5):1587-94.
Singh RS, Chauhan K, Kennedy JF. A panorama of bacterial inulinases: production, purification, characterization and industrial applications. International journal of biological macromolecules, (2017); 96(1):312-322.
Stern AL, Van der Verren SE, Näsvall J, Gutiérrez-de-Terán H, Selmer M. Structural mechanism of AadA, a dual-specificity aminoglycoside adenylyltransferase from Salmonella enterica. Journal of Biological Chemistry, (2018); 293(29):11481-90.
Gu S, Rumpel S, Zhou J, Strotmeier J, Bigalke H, Perry K, Shoemaker CB, Rummel A, Jin R. Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science, (2012); 335(6071):977-81.
Farrell DJ, Castanheira M, Chopra I. Characterization of global patterns and the genetics of fusidic acid resistance. Clinical infectious diseases, (2011); 52(suppl_7):S487-92.
Wassenaar T, Ussery D, Nielsen L, Ingmer H. Review and phylogenetic analysis of qac genes that reduce susceptibility to quaternary ammonium compounds in Staphylococcus species. European Journal of Microbiology and Immunology, (2015); 5(1):44-61.
Zhu J, He M, Xu W, Li Y, Huang R, Wu S, Niu H. Development of TEM-1 β-lactamase based protein translocation assay for identification of Anaplasma phagocytophilum type IV secretion system effector proteins. Scientific Reports, (2019); 9(1):4235.
Hunter JH, Gujjar R, Pang CK, Rathod PK. Kinetics and ligand-binding preferences of Mycobacterium tuberculosis thymidylate synthases, ThyA and ThyX. PloS one, (2008); 3(5):e2237.
Sharma K, Gupta M, Krupa A, Srinivasan N, Singh Y. EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and
phosphatase in Mycobacterium tuberculosis. The FEBS journal, (2006); 273(12): 2711-21.
Sharma K, Gupta M, Pathak M, Gupta N, Koul A, Sarangi S, Baweja R, Singh Y. Transcriptional control of the mycobacterial embCAB operon by PknH through a regulatory protein, EmbR, in vivo. Journal of bacteriology, (2006); 188(8):2936-44.
Morse JC, Girodat D, Burnett BJ, Holm M, Altman RB, Sanbonmatsu KY, Wieden HJ, Blanchard SC. Elongation factor-Tu can repetitively engage aminoacyl-tRNA within the ribosome during the proofreading stage of tRNA selection. Proceedings of the National Academy of Sciences, (2020); 117(7):3610-20.
Escuyer VE, Lety MA, Torrelles JB, Khoo KH, Tang JB, Rithner CD, Frehel C, McNeil MR, Brennan PJ, Chatterjee D. The role of the embA and embB gene products in the biosynthesis of the terminal hexaarabinofuranosyl motif of Mycobacterium smegmatisarabinogalactan. Journal of Biological Chemistry, (2001); 276(52):48854-62.
Berg S, Kaur D, Jackson M, Brennan PJ. The glycosyltransferases of Mycobacterium tuberculosis—roles in the synthesis of arabinogalactan, lipoarabinomannan, and other glycoconjugates. Glycobiology, (2007); 17(6):35R-56R.
Chakraborty S, Gruber T, Barry III CE, Boshoff HI, Rhee KY. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science, (2013); 339(6115):88-91.
Kremer L, Dover LG, Carrère S, Nampoothiri KM, Lesjean S, Brown AK, Brennan PJ, Minnikin DE, Locht C, Besra GS. Mycolic acid biosynthesis and enzymic characterization of the β-ketoacyl-ACP synthase A-condensing enzyme from Mycobacterium tuberculosis. Biochemical Journal, (2002); 364(2):423-30.
Aínsa JA, Pérez E, Pelicic V, Berthet FX, Gicquel B, Martín C. Aminoglycoside 2′‐N‐acetyltransferase genes are universally present in mycobacteria: characterization of the aac (2′)‐Ic gene from Mycobacterium tuberculosis and the aac (2′)‐Id gene from Mycobacterium smegmatis. Molecular microbiology, (1997); 24(2):431-41.
Newton GL, Koledin T, Gorovitz B, Rawat M, Fahey RC, Av-Gay Y. The glycosyltransferase gene encoding the enzyme catalyzing the first step of mycothiol biosynthesis (mshA). Journal of Bacteriology, (2003); 185(11):3476-9.
Colangeli R, Helb D, Sridharan S, Sun J, Varma‐Basil M, Hazbón MH, Harbacheuski R, Megjugorac NJ, Jacobs Jr WR, Holzenburg A, Sacchettini JC. The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drug tolerance to both isoniazid and ethambutol. Molecular microbiology, (2005); 55(6):1829-40.
Sørensen MA, Fricke J, Pedersen S. Ribosomal protein S1 is required for translation of most, if not all, natural mRNAs in Escherichia coli in vivo. Journal of molecular biology, (1998); 280(4): 561-9.
Aubry A, Pan XS, Fisher LM, Jarlier V, Cambau E. Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity. Antimicrobial agents and chemotherapy, (2004); 48(4):1281-8.
Mikheil DM, Shippy DC, Eakley NM, Okwumabua OE, Fadl AA. Deletion of gene encoding methyltransferase (gidB) confers high-level antimicrobial resistance in Salmonella. The Journal of antibiotics, (2012); 65(4):185-92.
Zeng S, Soetaert K, Ravon F, Vandeput M, Bald D, Kauffmann JM, Mathys V, Wattiez R, Fontaine V. Isoniazid bactericidal activity involves electron transport chain perturbation. Antimicrobial agents and chemotherapy, (2019); 63(3):10-128.
hang H, Deng JY, Bi LJ, Zhou YF, Zhang ZP, Zhang CG, Zhang Y, Zhang XE. Characterization of Mycobacterium tuberculosis nicotinamidase/pyrazinamidase. The FEBS journal, (2008); 275(4):753-62..
Fraaije MW, Kamerbeek NM, Heidekamp AJ, Fortin R, Janssen DB. The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer-Villiger monooxygenase. Journal of Biological Chemistry, (2004); 279(5):3354-60.
Jia H, Chu H, Dai G, Cao T, Sun Z. Rv1258c acts as a drug efflux pump and growth controlling factor in Mycobacterium tuberculosis. Tuberculosis, (2022); 133:102172.
Dzyubak E, Yap MN. The expression of antibiotic resistance methyltransferase correlates with mRNA stability independently of ribosome stalling. Antimicrobial agents and chemotherapy, (2016); 60(12):7178-88.
Kumar S, Parvathi A, Hernandez RL, Cadle KM, Varela MF. Identification of a novel UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) from Vibrio fischeri that confers high fosfomycin resistance in Escherichia coli. Archives of microbiology, (2009); 191:425-9.
Alland D, Kramnik I, Weisbrod TR, Otsubo L, Cerny R, Miller LP, Jacobs Jr WR, Bloom BR. Identification of differentially expressed mRNA in prokaryotic organisms by customized amplification libraries (DECAL): the effect of isoniazid on gene expression in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences, (1998); 95(22):13227-32.
Fassbinder F, Kist M, Bereswill S. Structural and functional analysis of the riboflavin synthesis genes encoding GTP cyclohydrolase II (ribA), DHBP synthase (ribBA), riboflavin synthase (ribC), and riboflavin deaminase/reductase (ribD) from Helicobacter pylori strain P1. FEMS microbiology letters, (2000); 191(2):191-7.
Madhusudan K, Nagaraja V. Mycobacterium smegmatis DNA gyrase: cloning and overexpression in Escherichia coli. Microbiology, (1995); 141(12):3029-37.
Rahman MA, Sobia P, Dwivedi VP, Bhawsar A, Singh DK, Sharma P, Moodley P, Van Kaer L, Bishai WR, Das G. Mycobacterium tuberculosis TlyA protein negatively regulates T helper (Th) 1 and Th17 differentiation and promotes tuberculosis pathogenesis. Journal of Biological Chemistry, (2015); 290(23):14407-17.
Doran JL, Pang Y, Mdluli KE, Moran AJ, Victor TC, Stokes RW, Mahenthiralingam E, Kreiswirth BN, Butt JL, Baron GS, Treit JD. Mycobacterium tuberculosis efpA encodes an efflux protein of the QacA transporter family. Clinical Diagnostic Laboratory Immunology, (1997); 4(1):23-32.
Holberger LE, Hayes CS. Ribosomal protein S12 and aminoglycoside antibiotics modulate A-site mRNA cleavage and transfer-messenger RNA activity in Escherichia coli. Journal of Biological Chemistry, (2009); 284(46):32188-200.
Singh R, Wiseman B, Deemagarn T, Jha V, Switala J, Loewen PC. Comparative study of catalase-peroxidases (KatGs). Archives of biochemistry and biophysics, (2008); 471(2):207-14.
Zhou YN, Lubkowska L, Hui M, Chen S, Strathern J, Jin DJ, Kashlev M. Isolation and characterization of RNA polymerase rpoB mutations that alter transcription slippage during elongation in Escherichia coli. Journal of Biological Chemistry, (2013); 288(4):2700-10.
Flores AR, Parsons LM, Pavelka Jr MS. Genetic analysis of the β-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics. Microbiology, (2005); 151(2):521-32.
Rifat M, Milton AH, Hall J, Oldmeadow C, Islam MA, Husain A, Akhanda MW, Siddiquea BN. Development of multidrug resistant tuberculosis in Bangladesh: a case-control study on risk factors. PloS one, (2014); 9(8):e105214.
Lomtadze N, Aspindzelashvili R, Janjgava M, Mirtskhulava V, Wright A, Blumberg HM, Salakaia A. Prevalence and risk factors for multidrug-resistant tuberculosis in the Republic of Georgia: a population-based study. The International journal of tuberculosis and lung disease, (2009); 13(1):68-73.
McQuaid CF, Horton KC, Dean AS, Knight GM, White RG. The risk of multidrug-or rifampicin-resistance in males versus females with tuberculosis. European Respiratory Journal, (2020); 56(3): 2000626.
Mulu W, Mekkonnen D, Yimer M, Admassu A, Abera B. Risk factors for multidrug resistant tuberculosis patients in Amhara National Regional State. African health sciences, (2015); 15(2):368-77.
De Martino M, Lodi L, Galli L, Chiappini E. Immune response to Mycobacterium tuberculosis: a narrative review. Frontiers in pediatric, (2019); 7: 350.
Mehari K, Asmelash T, Hailekiros H, Wubayehu T, Godefay H, Araya T, Saravanan M. Prevalence and factors associated with multidrug-resistant tuberculosis (MDR-TB) among presumptive MDR-TB patients in Tigray Region, Northern Ethiopia. Canadian Journal of Infectious Diseases and Medical Microbiology, (2019); 2019(1):1-8.
DOI: http://dx.doi.org/10.62940/als.v11i2.2048
Refbacks
- There are currently no refbacks.