{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T19:14:48Z","timestamp":1764962088205,"version":"3.46.0"},"reference-count":126,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00c3\u00a7\u00c3\u00a3o para a Ci\u00c3\u00aancia e a Tecnologia","doi-asserted-by":"publisher","award":["COMPETE2030-FEDER-00672000"],"award-info":[{"award-number":["COMPETE2030-FEDER-00672000"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00c3\u00a7\u00c3\u00a3o para a Ci\u00c3\u00aancia e a Tecnologia","doi-asserted-by":"publisher","award":["2022.00436.CEECIND"],"award-info":[{"award-number":["2022.00436.CEECIND"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00c3\u00a7\u00c3\u00a3o para a Ci\u00c3\u00aancia e a Tecnologia","doi-asserted-by":"publisher","award":["2023.00360.BD"],"award-info":[{"award-number":["2023.00360.BD"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Redundancy in biology is, at a glance, counterintuitive because if the function of two gene products completely overlaps then, throughout the course of evolution, one of the genes will likely accumulate mutations to the point of loss-of-function. The consensus is that partial functional overlap, for example, divergent secondary functions, play a major role in redundancy conservation. This asymmetrical nature offers a crucial advantage: phenotypic plasticity, which ensures that an essential cellular function can adapt to changes in the environment. In this context, the human pathogen\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    is an interesting example. Despite being an obligate pathogen that has been co-evolving with the human host for millennia,\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    genome retains redundant functions at multiple levels that allow the bacilli to adapt to extremely heterogeneous environments in the human host. This review explores how\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    functional redundancies mirror the heterogeneity of both intra- and extracellular host niches, with a focus on energy metabolism. Finally, we discuss the challenges and opportunities of functional redundancies in the context of drug development.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013749","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T18:47:14Z","timestamp":1764960434000},"page":"e1013749","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Essential redundancies fuel Mycobacterium tuberculosis adaptation to the host"],"prefix":"10.1371","volume":"21","author":[{"given":"Marco","family":"Silva","sequence":"first","affiliation":[]},{"given":"Alexandre J.","family":"Pinto","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7366-2107","authenticated-orcid":true,"given":"Tiago","family":"Beites","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"issue":"11","key":"ppat.1013749.ref001","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/0168-9525(93)90140-D","article-title":"Thinking about genetic redundancy","volume":"9","author":"JH Thomas","year":"1993","journal-title":"Trends Genet"},{"issue":"5","key":"ppat.1013749.ref002","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1006\/scdb.1999.0337","article-title":"Evolutionary preservation of redundant duplicated genes","volume":"10","author":"DC Krakauer","year":"1999","journal-title":"Semin Cell Dev Biol"},{"key":"ppat.1013749.ref003","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3389\/fcimb.2017.00467","article-title":"Beyond paralogs: the multiple layers of redundancy in bacterial pathogenesis","volume":"7","author":"S Ghosh","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"issue":"28","key":"ppat.1013749.ref004","doi-asserted-by":"crossref","first-page":"19329","DOI":"10.1074\/jbc.M800694200","article-title":"Biosynthesis and recycling of nicotinamide cofactors in Mycobacterium tuberculosis. An essential role for NAD in nonreplicating bacilli","volume":"283","author":"HIM Boshoff","year":"2008","journal-title":"J Biol Chem"},{"issue":"2","key":"ppat.1013749.ref005","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/evl3.277","article-title":"From genotype to phenotype: genetic redundancy and the maintenance of an adaptive polymorphism in the context of high gene flow","volume":"6","author":"T Bataillon","year":"2022","journal-title":"Evol Lett"},{"issue":"8","key":"ppat.1013749.ref006","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1073\/pnas.0730515100","article-title":"Essential Bacillus subtilis genes","volume":"100","author":"K Kobayashi","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1013749.ref007","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02133-16","article-title":"Comprehensive essentiality analysis of the Mycobacterium tuberculosis genome via saturating transposon mutagenesis","volume":"8","author":"MA DeJesus","year":"2017","journal-title":"mBio"},{"issue":"17","key":"ppat.1013749.ref008","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2021.06.033","article-title":"Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis","volume":"184","author":"B Bosch","year":"2021","journal-title":"Cell"},{"issue":"4","key":"ppat.1013749.ref009","doi-asserted-by":"crossref","DOI":"10.1128\/mSystems.00070-19","article-title":"Genomewide assessment of Mycobacterium tuberculosis conditionally essential metabolic pathways","volume":"4","author":"Y Minato","year":"2019","journal-title":"mSystems"},{"issue":"6","key":"ppat.1013749.ref010","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.cell.2013.10.045","article-title":"Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing","volume":"155","author":"YJ Zhang","year":"2013","journal-title":"Cell"},{"key":"ppat.1013749.ref011","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.74419","article-title":"Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice","volume":"11","author":"CM Smith","year":"2022","journal-title":"Elife"},{"issue":"48","key":"ppat.1013749.ref012","doi-asserted-by":"crossref","first-page":"14888","DOI":"10.1073\/pnas.1505587112","article-title":"The extent of functional redundancy changes as species\u2019 roles shift in different environments","volume":"112","author":"I Fetzer","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6685","key":"ppat.1013749.ref013","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/31159","article-title":"Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence","volume":"393","author":"ST Cole","year":"1998","journal-title":"Nature"},{"issue":"6823","key":"ppat.1013749.ref014","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/35059006","article-title":"Massive gene decay in the leprosy bacillus","volume":"409","author":"ST Cole","year":"2001","journal-title":"Nature"},{"key":"ppat.1013749.ref015","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12890-016-0185-5","article-title":"Mycobacteria infect different cell types in the human lung and cause species dependent cellular changes in infected cells","volume":"16","author":"D Ganbat","year":"2016","journal-title":"BMC Pulm Med"},{"issue":"3","key":"ppat.1013749.ref016","doi-asserted-by":"crossref","DOI":"10.1128\/CMR.00159-19","article-title":"Caseum: a niche for Mycobacterium tuberculosis drug-tolerant persisters","volume":"33","author":"JP Sarathy","year":"2020","journal-title":"Clin Microbiol 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Lu","year":"2019","journal-title":"Int J Genomics"},{"key":"ppat.1013749.ref024","doi-asserted-by":"crossref","first-page":"100384","DOI":"10.1016\/j.coisb.2021.100384","article-title":"Convergence and divergence in the metabolic network of Mycobacterium tuberculosis","volume":"28","author":"CB Hubert","year":"2021","journal-title":"Curr Opin Syst Biol"},{"issue":"2","key":"ppat.1013749.ref025","doi-asserted-by":"crossref","DOI":"10.1093\/femsre\/fuae006","article-title":"Evolution and emergence of Mycobacterium tuberculosis","volume":"48","author":"M Orgeur","year":"2024","journal-title":"FEMS Microbiol Rev"},{"issue":"1","key":"ppat.1013749.ref026","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1111\/imr.12252","article-title":"Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses","volume":"264","author":"A Lenaerts","year":"2015","journal-title":"Immunol 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Via","year":"2008","journal-title":"Infect Immun"},{"issue":"4","key":"ppat.1013749.ref049","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s10439-015-1415-3","article-title":"Mathematical model of oxygen transport in tuberculosis granulomas","volume":"44","author":"M Datta","year":"2016","journal-title":"Ann Biomed Eng"},{"issue":"12","key":"ppat.1013749.ref050","article-title":"A lysine acetyltransferase contributes to the metabolic adaptation to hypoxia in Mycobacterium tuberculosis","volume":"25","author":"ESC Rittershaus","year":"2018","journal-title":"Cell Chem Biol"},{"issue":"8","key":"ppat.1013749.ref051","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1161\/01.ATV.0000229665.78997.0b","article-title":"Hypoxia converts human macrophages into triglyceride-loaded foam cells","volume":"26","author":"P Bostr\u00f6m","year":"2006","journal-title":"Arterioscler Thromb Vasc 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Beites","year":"2019","journal-title":"Nat Commun"},{"key":"ppat.1013749.ref076","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.71946","article-title":"De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis","volume":"10","author":"T Laval","year":"2021","journal-title":"Elife"},{"key":"ppat.1013749.ref077","doi-asserted-by":"crossref","first-page":"106377","DOI":"10.1016\/j.pep.2023.106377","article-title":"Recombinant expression and functional characterization of FadD2 protein in Mycobacterium tuberculosis","volume":"214","author":"D Liu","year":"2024","journal-title":"Protein Expr Purif"},{"issue":"8","key":"ppat.1013749.ref078","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1086\/651452","article-title":"Attenuation of Mycobacterium tuberculosis functionally disrupted in a fatty acyl-coenzyme A synthetase gene fadD5","volume":"201","author":"KY Dunphy","year":"2010","journal-title":"J Infect 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isomerase","volume":"22","author":"S Srivastava","year":"2015","journal-title":"Chem Biol"},{"key":"ppat.1013749.ref085","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1099\/mic.0.038802-0","article-title":"Characterization of a beta-hydroxybutyryl-CoA dehydrogenase from Mycobacterium tuberculosis","volume":"156","author":"RC Taylor","year":"2010","journal-title":"Microbiology (Reading)"},{"key":"ppat.1013749.ref086","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1107\/S2059798318017242","article-title":"Crystal structure of Mycobacterium tuberculosis FadB2 implicated in mycobacterial \u03b2-oxidation","volume":"75","author":"JAG Cox","year":"2019","journal-title":"Acta Crystallogr D Struct Biol"},{"issue":"16","key":"ppat.1013749.ref087","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1111\/febs.16792","article-title":"Crystal structure of FadA2 thiolase from Mycobacterium tuberculosis and prediction of its substrate specificity and membrane-anchoring 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1,4-dihydroxy-2-naphthoate [corrected] prenyltransferase inhibitors: new drug leads for multidrug-resistant gram-positive pathogens","volume":"50","author":"M Kurosu","year":"2007","journal-title":"J Med Chem"},{"key":"ppat.1013749.ref101","doi-asserted-by":"crossref","first-page":"115125","DOI":"10.1016\/j.ejmech.2023.115125","article-title":"SAR study of piperidine derivatives as inhibitors of 1,4-dihydroxy-2-naphthoate isoprenyltransferase (MenA) from Mycobacterium tuberculosis","volume":"249","author":"K Berg","year":"2023","journal-title":"Eur J Med Chem"},{"issue":"1","key":"ppat.1013749.ref102","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02022-16","article-title":"A novel small-molecule inhibitor of the Mycobacterium tuberculosis demethylmenaquinone methyltransferase MenG is bactericidal to both growing and nutritionally deprived persister cells","volume":"8","author":"P Sukheja","year":"2017","journal-title":"mBio"},{"issue":"5","key":"ppat.1013749.ref103","doi-asserted-by":"crossref","first-page":"5774","DOI":"10.1021\/acs.jmedchem.4c03156","article-title":"Evolution of small molecule inhibitors of Mycobacterium tuberculosis menaquinone biosynthesis","volume":"68","author":"P Sharma","year":"2025","journal-title":"J Med Chem"},{"issue":"4","key":"ppat.1013749.ref104","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.molcel.2015.10.016","article-title":"Polyketide quinones are alternate intermediate electron carriers during mycobacterial respiration in oxygen-deficient niches","volume":"60","author":"A Anand","year":"2015","journal-title":"Mol Cell"},{"issue":"1","key":"ppat.1013749.ref105","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1038\/s41467-021-21748-6","article-title":"Biofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis","volume":"12","author":"P Chakraborty","year":"2021","journal-title":"Nat Commun"},{"issue":"9","key":"ppat.1013749.ref106","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/nm.3262","article-title":"Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis","volume":"19","author":"K Pethe","year":"2013","journal-title":"Nat Med"},{"issue":"28","key":"ppat.1013749.ref107","doi-asserted-by":"crossref","first-page":"7426","DOI":"10.1073\/pnas.1706139114","article-title":"Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection","volume":"114","author":"NP Kalia","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1013749.ref108","article-title":"Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis","volume":"13","author":"BS Lee","year":"2021","journal-title":"EMBO Mol 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