{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T06:38:06Z","timestamp":1774334286754,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T00:00:00Z","timestamp":1694563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001655","name":"DAAD","doi-asserted-by":"publisher","award":["57507869"],"award-info":[{"award-number":["57507869"]}],"id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tuberculosis remains the leading cause of death from a single pathogen. On the other hand, antimicrobial resistance (AMR) makes it increasingly difficult to deal with this disease. We present the hyperbolic embedding of the Mycobacterium tuberculosis protein interaction network (mtbPIN) of resistant strain (MTB XDR1219) to determine the biological relevance of its latent geometry. In this hypermap, proteins with similar interacting partners occupy close positions. An analysis of the hypermap of available drug targets (DTs) and their direct and intermediate interactors was used to identify potentially useful drug combinations and drug targets. We identify rpsA and rpsL as close DTs targeted by different drugs (pyrazinamide and aminoglycosides, respectively) and propose that the combination of these drugs could have a synergistic effect. We also used the hypermap to explain the effects of drugs that affect multiple DTs, for example, forcing the bacteria to deal with multiple stresses like ethambutol, which affects the synthesis of both arabinogalactan and lipoarabinomannan. Our strategy uncovers novel potential DTs, such as dprE1 and dnaK proteins, which interact with two close DT pairs: arabinosyltransferases (embC and embB), Ser\/Thr protein kinase (pknB) and RNA polymerase (rpoB), respectively. Our approach provides mechanistic explanations for existing drugs and suggests new DTs. This strategy can also be applied to the study of other resistant strains.<\/jats:p>","DOI":"10.3390\/ijms241814050","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T09:57:56Z","timestamp":1694685476000},"page":"14050","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Selection of Multi-Drug Targets against Drug-Resistant Mycobacterium tuberculosis XDR1219 Using the Hyperbolic Mapping of the Protein Interaction Network"],"prefix":"10.3390","volume":"24","author":[{"given":"Noor ul Ain","family":"Zahra","sequence":"first","affiliation":[{"name":"Lab 103 PCMD ext., Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"},{"name":"Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University, Hans-Dieter-H\u00fcsch-Weg 15, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aimilia-Christina","family":"Vagiona","sequence":"additional","affiliation":[{"name":"Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University, Hans-Dieter-H\u00fcsch-Weg 15, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9928-4482","authenticated-orcid":false,"given":"Reaz","family":"Uddin","sequence":"additional","affiliation":[{"name":"Lab 103 PCMD ext., Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-1711","authenticated-orcid":false,"given":"Miguel A.","family":"Andrade-Navarro","sequence":"additional","affiliation":[{"name":"Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University, Hans-Dieter-H\u00fcsch-Weg 15, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1016\/j.apsb.2022.04.014","article-title":"Overcoming Mycobacterium tuberculosis through Small Molecule Inhibitors to Break down Cell Wall Synthesis","volume":"12","author":"Kuang","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_2","unstructured":"WHO (2020). Global Tuberculosis Report 2020, WHO."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e43","DOI":"10.3346\/jkms.2023.38.e43","article-title":"Impact of COVID-19 Pandemic on Tuberculosis Preventive Services and Their Post-Pandemic Recovery Strategies: A Rapid Review of Literature","volume":"38","author":"Jeong","year":"2023","journal-title":"J. Korean Med. Sci."},{"key":"ref_4","unstructured":"WHO World Health Organization (2021). Global Tuberculosis Report 2021, World Health Organization."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7489","DOI":"10.1021\/acs.jmedchem.2c00227","article-title":"Tuberculosis Drug Discovery: Challenges and New Horizons","volume":"65","author":"Fernandes","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"871464","DOI":"10.3389\/fmicb.2022.871464","article-title":"Editorial: Approaches to Address Resistance, Drug Discovery, and Vaccine Development in Mycobacterium tuberculosis: Challenges and Opportunities","volume":"13","author":"Sharma","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1146\/annurev-pathol-042120-032916","article-title":"Perspectives and Advances in the Understanding of Tuberculosis","volume":"16","author":"Kinsella","year":"2021","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/s41579-022-00731-y","article-title":"Anti-Tuberculosis Treatment Strategies and Drug Development: Challenges and Priorities","volume":"20","author":"Dartois","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1128\/CMR.00030-10","article-title":"Challenges of Antibacterial Discovery","volume":"24","author":"Silver","year":"2011","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.mib.2020.06.009","article-title":"An Overview of the Global Antimicrobial Resistance Research and Development Hub and the Current Landscape","volume":"57","author":"Mattar","year":"2020","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e8792","DOI":"10.15252\/msb.20188792","article-title":"Mass Spectrometry-based Protein\u2013Protein Interaction Networks for the Study of Human Diseases","volume":"17","author":"Richards","year":"2021","journal-title":"Mol. Syst. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/ng.3168","article-title":"Pan-Cancer Network Analysis Identifies Combinations of Rare Somatic Mutations across Pathways and Protein Complexes","volume":"47","author":"Leiserson","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ymeth.2010.08.007","article-title":"Purification and Characterization of HIV\u2013Human Protein Complexes","volume":"53","author":"Gulbahce","year":"2011","journal-title":"Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41392-020-00315-3","article-title":"Recent Advances in the Development of Protein\u2013Protein Interactions Modulators: Mechanisms and Clinical Trials","volume":"5","author":"Lu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/nmeth.2131","article-title":"A High-Throughput Approach for Measuring Temporal Changes in the Interactome","volume":"9","author":"Kristensen","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/s41598-021-04379-1","article-title":"Generalised Popularity-Similarity Optimisation Model for Growing Hyperbolic Networks beyond Two Dimensions","volume":"12","author":"Balogh","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1093\/bioinformatics\/bty206","article-title":"The Latent Geometry of the Human Protein Interaction Network","volume":"34","author":"Mier","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nature11459","article-title":"Popularity versus Similarity in Growing Networks","volume":"489","author":"Papadopoulos","year":"2012","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"036106","DOI":"10.1103\/PhysRevE.82.036106","article-title":"Hyperbolic Geometry of Complex Networks","volume":"82","author":"Krioukov","year":"2010","journal-title":"Phys. Rev. E"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1109\/TNET.2013.2294052","article-title":"Network Mapping by Replaying Hyperbolic Growth","volume":"23","author":"Papadopoulos","year":"2015","journal-title":"IEEE\/ACM Trans. Netw."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8350","DOI":"10.1038\/s41598-021-87333-5","article-title":"Optimisation of the Coalescent Hyperbolic Embedding of Complex Networks","volume":"11","author":"Palla","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1038\/s41467-017-01825-5","article-title":"Machine Learning Meets Complex Networks via Coalescent Embedding in the Hyperbolic Space","volume":"8","author":"Muscoloni","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Vagiona, A.-C., Mier, P., Petrakis, S., and Andrade-Navarro, M.A. (2022). Analysis of Huntington\u2019s Disease Modifiers Using the Hyperbolic Mapping of the Protein Interaction Network. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105853"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1007\/s12033-021-00377-w","article-title":"Protein Integrated Network Analysis to Reveal Potential Drug Targets Against Extended Drug-Resistant Mycobacterium tuberculosis XDR1219","volume":"63","author":"Zahra","year":"2021","journal-title":"Mol. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"30108","DOI":"10.1038\/srep30108","article-title":"Efficient Embedding of Complex Networks to Hyperbolic Space via Their Laplacian","volume":"6","author":"Mier","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"022807","DOI":"10.1103\/PhysRevE.92.022807","article-title":"Network Geometry Inference Using Common Neighbors","volume":"92","author":"Papadopoulos","year":"2015","journal-title":"Phys. Rev. E"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Monama, M.Z., Olotu, F., and Tastan Bishop, \u00d6. (2023). Investigation of Multi-Subunit Mycobacterium tuberculosis DNA-Directed RNA Polymerase and Its Rifampicin Resistant Mutants. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043313"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1126\/science.aba9102","article-title":"Structures of Cell Wall Arabinosyltransferases with the Anti-Tuberculosis Drug Ethambutol","volume":"368","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/AAC.01279-17","article-title":"Mutations within EmbCAB Are Associated with Variable Level of Ethambutol Resistance in Mycobacterium tuberculosis Isolates from China","volume":"62","author":"Sun","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"717045","DOI":"10.3389\/fmicb.2021.717045","article-title":"Mechanism of Action, Resistance, Synergism, and Clinical Implications of Delamanid Against Multidrug-Resistant Mycobacterium tuberculosis","volume":"12","author":"Khoshnood","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.2174\/2210298101666210108105814","article-title":"Computational Insight into the Binding Mechanism of Pyrazinoic Acid to RpsA Protein","volume":"1","author":"Rehman","year":"2021","journal-title":"Curr. Chin. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yang, W., and Hu, F. (2022). Research Updates of Plasmid-Mediated Aminoglycoside Resistance 16S RRNA Methyltransferase. Antibiotics, 11.","DOI":"10.3390\/antibiotics11070906"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1093\/jac\/dkaa136","article-title":"Systematic Review of Mutations Associated with Resistance to the New and Repurposed Mycobacterium tuberculosis Drugs Bedaquiline, Clofazimine, Linezolid, Delamanid and Pretomanid","volume":"75","author":"Kadura","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1021\/acsinfecdis.0c00001","article-title":"Multitarget Approaches against Multi-Resistant Superbugs","volume":"6","author":"Gray","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6135","DOI":"10.1038\/s41598-017-06415-5","article-title":"Anti-Tubercular Activity of Pyrazinamide Is Independent of Trans-Translation and RpsA","volume":"7","author":"Dillon","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41467-019-14238-3","article-title":"The Molecular Basis of Pyrazinamide Activity on Mycobacterium tuberculosis PanD","volume":"11","author":"Sun","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4689","DOI":"10.2147\/IDR.S332835","article-title":"In Vitro Antimicrobial Activity Comparison of Linezolid, Tedizolid, Sutezolid and Delpazolid Against Slowly Growing Mycobacteria Isolated in Beijing, China","volume":"14","author":"Yu","year":"2021","journal-title":"Infect. Drug Resist."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.tips.2019.10.005","article-title":"Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide","volume":"40","author":"Gopal","year":"2019","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1093\/jac\/dkab505","article-title":"Delamanid or Pretomanid? A Solomonic Judgement!","volume":"77","author":"Mudde","year":"2022","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_40","first-page":"1","article-title":"Linezolid for Drug-Resistant Pulmonary Tuberculosis","volume":"3","author":"Singh","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2100621","DOI":"10.1183\/13993003.00621-2021","article-title":"Emergence of Bedaquiline Resistance in a High Tuberculosis Burden Country","volume":"59","author":"Chesov","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14499","DOI":"10.1002\/jcb.28711","article-title":"Impact of Bedaquiline and Capreomycin on the Gene Expression Patterns of Multidrug-resistant Mycobacterium tuberculosis H37Rv Strain and Understanding the Molecular Mechanism of Antibiotic Resistance","volume":"120","author":"Miryala","year":"2019","journal-title":"J. Cell Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Bhargavi, G., Singh, A.K., Deenadayalan, A., Ponnuraja, C., Patil, S.A., and Palaniyandi, K. (2022). Role of a Putative Alkylhydroperoxidase Rv2159c in the Oxidative Stress Response and Virulence of Mycobacterium tuberculosis. Pathogens, 11.","DOI":"10.3390\/pathogens11060684"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/mBio.00123-21","article-title":"The DnaK Chaperone System Buffers the Fitness Cost of Antibiotic Resistance Mutations in Mycobacteria","volume":"12","author":"Fay","year":"2021","journal-title":"mBio"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12393","DOI":"10.1038\/ncomms12393","article-title":"Turning the Respiratory Flexibility of Mycobacterium tuberculosis against Itself","volume":"7","author":"Lamprecht","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e25624","DOI":"10.7554\/eLife.25624","article-title":"Efficacy of \u03b2-Lactam\/\u03b2-Lactamase Inhibitor Combination Is Linked to WhiB4-Mediated Changes in Redox Physiology of Mycobacterium tuberculosis","volume":"6","author":"Mishra","year":"2017","journal-title":"eLife"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Niranjan, V., Uttarkar, A., Murali, K., Niranjan, S., Gopal, J., and Kumar, J. (2022). Mycobacterium Time-Series Genome Analysis Identifies AAC2\u2032 as a Potential Drug Target with Naloxone Showing Potential Bait Drug Synergism. Molecules, 27.","DOI":"10.3390\/molecules27196150"},{"key":"ref_48","first-page":"1110","article-title":"Functional Reconstitution of the Mycobacterium tuberculosis Long-chain Acyl-CoA Carboxylase from Multiple Acyl-CoA Subunits","volume":"284","author":"Diacovich","year":"2017","journal-title":"Fed. Eur. Biochem. Soc. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1093\/infdis\/jiz542","article-title":"Impaired Alanine Transport or Exposure to D-Cycloserine Increases the Susceptibility of MRSA to \u03b2-Lactam Antibiotics","volume":"221","author":"Gallagher","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ijid.2016.08.027","article-title":"Interactions of Linezolid and Second-Line Anti-Tuberculosis Agents against Multidrug-Resistant Mycobacterium tuberculosis in Vitro and in Vivo","volume":"52","author":"Zhao","year":"2016","journal-title":"Int. J. Infect. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"106509","DOI":"10.1016\/j.ijantimicag.2021.106509","article-title":"Evaluating the Effect of Clofazimine against Mycobacterium tuberculosis given Alone or in Combination with Pretomanid, Bedaquiline or Linezolid","volume":"59","author":"Kim","year":"2022","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1194\/jlr.RA120000747","article-title":"The Protein Kinase PknB Negatively Regulates Biosynthesis and Trafficking of Mycolic Acids in Mycobacteria","volume":"61","author":"Le","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Sun, M., Ge, S., and Li, Z. (2022). The Role of Phosphorylation and Acylation in the Regulation of Drug Resistance in Mycobacterium tuberculosis. Biomedicines, 10.","DOI":"10.3390\/biomedicines10102592"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1080\/20477724.2021.1928870","article-title":"Significance of the Coexistence of Non-Codon 315 KatG, InhA, and OxyR-AhpC Intergenic Gene Mutations among Isoniazid-Resistant and Multidrug-Resistant Isolates of Mycobacterium tuberculosis: A Report of Novel Mutations","volume":"116","author":"Norouzi","year":"2022","journal-title":"Pathog. Glob. Health"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Isakova, J., Sovkhozova, N., Vinnikov, D., Goncharova, Z., Talaibekova, E., Aldasheva, N., and Aldashev, A. (2018). Mutations of RpoB, KatG, InhA and Ahp Genes in Rifampicin and Isoniazid-Resistant Mycobacterium tuberculosis in Kyrgyz Republic. BMC Microbiol., 18.","DOI":"10.1186\/s12866-018-1168-x"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4119","DOI":"10.2147\/IDR.S333433","article-title":"RpoB Mutations and Effects on Rifampin Resistance in Mycobacterium tuberculosis","volume":"14","author":"Li","year":"2021","journal-title":"Infect. Drug Resist."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6181","DOI":"10.1007\/s11033-021-06611-7","article-title":"Latent Tuberculosis: Interaction of Virulence Factors in Mycobacterium tuberculosis","volume":"48","author":"Sundararajan","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/nrmicro2319","article-title":"Antibiotic Resistance and Its Cost: Is It Possible to Reverse Resistance?","volume":"8","author":"Andersson","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.mib.2006.07.002","article-title":"The Biological Cost of Mutational Antibiotic Resistance: Any Practical Conclusions?","volume":"9","author":"Andersson","year":"2006","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"206","DOI":"10.3390\/antibiotics2020206","article-title":"Rifampicin Resistance: Fitness Costs and the Significance of Compensatory Evolution","volume":"2","author":"Hughes","year":"2013","journal-title":"Antibiotics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1126\/science.1118370","article-title":"Hsp90 Potentiates the Rapid Evolution of New Traits: Drug Resistance in Diverse Fungi","volume":"309","author":"Cowen","year":"2005","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3105","DOI":"10.1038\/s41467-020-16932-z","article-title":"and F.B. and B.T. Highly Parallel Lab Evolution Reveals That Epistasis Can Curb the Evolution of Antibiotic Resistance","volume":"11","author":"Lukacisinova","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1093\/gbe\/evw176","article-title":"The Molecular Chaperone DnaK Is a Source of Mutational Robustness","volume":"8","author":"Berlanga","year":"2016","journal-title":"Genome Biol. Evol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/nrc1716","article-title":"HSP90 and the Chaperoning of Cancer","volume":"5","author":"Whitesell","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1038\/ng1676","article-title":"Genomic Buffering Mitigates the Effects of Deleterious Mutations in Bacteria","volume":"37","author":"Roth","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1111\/j.1365-2958.2008.06583.x","article-title":"Genome-Wide Regulon and Crystal Structure of BlaI (Rv1846c) from Mycobacterium tuberculosis","volume":"71","author":"Sala","year":"2009","journal-title":"Mol. Microbiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5099312","DOI":"10.1155\/2022\/5099312","article-title":"Advances in Key Drug Target Identification and New Drug Development for Tuberculosis","volume":"2022","author":"Mi","year":"2022","journal-title":"Biomed. Res. Int."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Ezquerra-Azn\u00e1rez, J.M., Degiacomi, G., Ga\u0161parovi\u010d, H., Stelitano, G., Sammartino, J.C., Kordul\u00e1kov\u00e1, J., Governa, P., Manetti, F., Pasca, M.R., and Chiarelli, L.R. (2022). The Veterinary Anti-Parasitic Selamectin Is a Novel Inhibitor of the Mycobacterium tuberculosis DprE1 Enzyme. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020771"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.chembiol.2021.11.004","article-title":"An Allosteric Inhibitor of Bacterial Hsp70 Chaperone Potentiates Antibiotics and Mitigates Resistance","volume":"29","author":"Hosfelt","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.chembiol.2022.05.002","article-title":"Multi-Protein Complexes as Drug Targets","volume":"29","author":"Gestwicki","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"D501","DOI":"10.1093\/nar\/gki025","article-title":"NCBI Reference Sequence (RefSeq): A Curated Non-Redundant Sequence Database of Genomes, Transcripts and Proteins","volume":"33","author":"Pruitt","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING Database in 2021: Customizable Protein\u2013Protein Networks, and Functional Characterization of User-Uploaded Gene\/Measurement Sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A Major Update to the DrugBank Database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_74","first-page":"D1031","article-title":"Therapeutic Target Database 2020: Enriched Resource for Facilitating Research and Early Development of Targeted Therapeutics","volume":"48","author":"Wang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"100355","DOI":"10.1016\/j.plgene.2022.100355","article-title":"Using Ortholog Information from Multiple Species to Predict Barley Protein-Protein Interaction Network","volume":"30","author":"Hekmati","year":"2022","journal-title":"Plant Gene"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s41109-016-0013-0","article-title":"Manifold Learning and Maximum Likelihood Estimation for Hyperbolic Network Embedding","volume":"1","author":"Mier","year":"2016","journal-title":"Appl. Netw. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: Tool for the Unification of Biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14050\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:50:23Z","timestamp":1760129423000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,13]]},"references-count":77,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241814050"],"URL":"https:\/\/doi.org\/10.3390\/ijms241814050","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,13]]}}}