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Identification of KasA as the cellular target of an anti-tubercular scaffold.

Abrahams KA, Chung CW, Ghidelli-Disse S, Rullas J, Rebollo-López MJ, Gurcha SS, Cox JA, Mendoza A, Jiménez-Navarro E, Martínez-Martínez MS, Neu M, Shillings A, Homes P, Argyrou A, Casanueva R, Loman NJ, Moynihan PJ, Lelièvre J, Selenski C, Axtman M, Kremer L, Bantscheff M, Angulo-Barturen I, Izquierdo MC, Cammack NC, Drewes G, Ballell L, Barros D, Besra GS, Bates RH
Nat Commun 7 12581 (2016)
Cited: 47 times
EuropePMC logo PMID: 27581223

Abstract

Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related β-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.

Reviews - 5ld8 mentioned but not cited (2)

  1. Antibiotics and resistance: the two-sided coin of the mycobacterial cell wall. Batt SM, Burke CE, Moorey AR, Besra GS. Cell Surf 6 100044 (2020)
  2. Mycobacterium tuberculosis KasA as a drug target: Structure-based inhibitor design. Rudraraju RS, Daher SS, Gallardo-Macias R, Wang X, Neiditch MB, Freundlich JS. Front Cell Infect Microbiol 12 1008213 (2022)

Articles - 5ld8 mentioned but not cited (1)

  1. Identification of KasA as the cellular target of an anti-tubercular scaffold. Abrahams KA, Chung CW, Ghidelli-Disse S, Rullas J, Rebollo-López MJ, Gurcha SS, Cox JA, Mendoza A, Jiménez-Navarro E, Martínez-Martínez MS, Neu M, Shillings A, Homes P, Argyrou A, Casanueva R, Loman NJ, Moynihan PJ, Lelièvre J, Selenski C, Axtman M, Kremer L, Bantscheff M, Angulo-Barturen I, Izquierdo MC, Cammack NC, Drewes G, Ballell L, Barros D, Besra GS, Bates RH. Nat Commun 7 12581 (2016)


Reviews citing this publication (16)

  1. Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target. Abrahams KA, Besra GS. Parasitology 145 116-133 (2018)
  2. Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets. Oh S, Trifonov L, Yadav VD, Barry CE, Boshoff HI. Front Cell Infect Microbiol 11 611304 (2021)
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  4. Mycobacterial drug discovery. Abrahams KA, Besra GS. RSC Med Chem 11 1354-1365 (2020)
  5. Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets. Shaku M, Ealand C, Kana BD. Front Cell Infect Microbiol 10 603382 (2020)
  6. Recent Progress in the Development of Novel Mycobacterium Cell Wall Inhibitor to Combat Drug-Resistant Tuberculosis. Belete TM. Microbiol Insights 15 11786361221099878 (2022)
  7. Mycobacterium tuberculosis: Pathogenesis and therapeutic targets. Yang J, Zhang L, Qiao W, Luo Y. MedComm (2020) 4 e353 (2023)
  8. A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs. Bibens L, Becker JP, Dassonville-Klimpt A, Sonnet P. Pharmaceuticals (Basel) 16 425 (2023)
  9. An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis. Mori M, Villa S, Ciceri S, Colombo D, Ferraboschi P, Meneghetti F. Molecules 26 7082 (2021)
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  12. Integrated genomics and chemical biology herald an era of sophisticated antibacterial discovery, from defining essential genes to target elucidation. Warrier T, Romano KP, Clatworthy AE, Hung DT. Cell Chem Biol 29 716-729 (2022)
  13. Target Identification in Anti-Tuberculosis Drug Discovery. Capela R, Félix R, Clariano M, Nunes D, Perry MJ, Lopes F. Int J Mol Sci 24 10482 (2023)
  14. The Role of Phosphorylation and Acylation in the Regulation of Drug Resistance in Mycobacterium tuberculosis. Sun M, Ge S, Li Z. Biomedicines 10 2592 (2022)
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Articles citing this publication (28)

  1. CRISPRi chemical genetics and comparative genomics identify genes mediating drug potency in Mycobacterium tuberculosis. Li S, Poulton NC, Chang JS, Azadian ZA, DeJesus MA, Ruecker N, Zimmerman MD, Eckartt KA, Bosch B, Engelhart CA, Sullivan DF, Gengenbacher M, Dartois VA, Schnappinger D, Rock JM. Nat Microbiol 7 766-779 (2022)
  2. Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets. Trofimov V, Kicka S, Mucaria S, Hanna N, Ramon-Olayo F, Del Peral LV, Lelièvre J, Ballell L, Scapozza L, Besra GS, Cox JAG, Soldati T. Sci Rep 8 3939 (2018)
  3. Computational Approaches to Identify Molecules Binding to Mycobacterium tuberculosis KasA. Puhl AC, Lane TR, Vignaux PA, Zorn KM, Capodagli GC, Neiditch MB, Freundlich JS, Ekins S. ACS Omega 5 29935-29942 (2020)
  4. Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors. Sabbah M, Mendes V, Vistal RG, Dias DMG, Záhorszká M, Mikušová K, Korduláková J, Coyne AG, Blundell TL, Abell C. J Med Chem 63 4749-4761 (2020)
  5. Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface. Abrahams KA, Cox JAG, Fütterer K, Rullas J, Ortega-Muro F, Loman NJ, Moynihan PJ, Pérez-Herrán E, Jiménez E, Esquivias J, Barros D, Ballell L, Alemparte C, Besra GS. Sci Rep 7 9430 (2017)
  6. Modular Synthesis of Diverse Natural Product-Like Macrocycles: Discovery of Hits with Antimycobacterial Activity. Dow M, Marchetti F, Abrahams KA, Vaz L, Besra GS, Warriner S, Nelson A. Chemistry 23 7207-7211 (2017)
  7. Accelerating Early Antituberculosis Drug Discovery by Creating Mycobacterial Indicator Strains That Predict Mode of Action. Boot M, Commandeur S, Subudhi AK, Bahira M, Smith TC, Abdallah AM, van Gemert M, Lelièvre J, Ballell L, Aldridge BB, Pain A, Speer A, Bitter W. Antimicrob. Agents Chemother. 62 (2018)
  8. Colworth prize lecture 2016: exploiting new biological targets from a whole-cell phenotypic screening campaign for TB drug discovery. Moynihan PJ, Besra GS. Microbiology (Reading, Engl.) 163 1385-1388 (2017)
  9. A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA. Inoyama D, Awasthi D, Capodagli GC, Tsotetsi K, Sukheja P, Zimmerman M, Li SG, Jadhav R, Russo R, Wang X, Grady C, Richmann T, Shrestha R, Li L, Ahn YM, Ho Liang HP, Mina M, Park S, Perlin DS, Connell N, Dartois V, Alland D, Neiditch MB, Kumar P, Freundlich JS. Cell Chem Biol 27 560-570.e10 (2020)
  10. Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis. Kidwai S, Park CY, Mawatwal S, Tiwari P, Jung MG, Gosain TP, Kumar P, Alland D, Kumar S, Bajaj A, Hwang YK, Song CS, Dhiman R, Lee IY, Singh R. Antimicrob. Agents Chemother. 61 (2017)
  11. Genome analyses of 174 strains of Mycobacterium tuberculosis provide insight into the evolution of drug resistance and reveal potential drug targets. Verma H, Nagar S, Vohra S, Pandey S, Lal D, Negi RK, Lal R, Rawat CD. Microb Genom 7 (2021)
  12. Novel Sulfamethoxazole Ureas and Oxalamide as Potential Antimycobacterial Agents. Krátký M, Stolaříková J, Vinšová J. Molecules 22 (2017)
  13. 1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis. Singh V, Grzegorzewicz AE, Fienberg S, Müller R, Khonde LP, Sanz O, Alfonso S, Urones B, Drewes G, Bantscheff M, Ghidelli-Disse S, Ioerger TR, Angala B, Liu J, Lee RE, Sacchettini JC, Krieger IV, Jackson M, Chibale K, Ghorpade SR. ACS Infect Dis 8 2315-2326 (2022)
  14. Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics. Venugopala KN, Kandeel M, Pillay M, Deb PK, Abdallah HH, Mahomoodally MF, Chopra D. Antibiotics (Basel) 9 (2020)
  15. Anti-tubercular derivatives of rhein require activation by the monoglyceride lipase Rv0183. Abrahams KA, Hu W, Li G, Lu Y, Richardson EJ, Loman NJ, Huang H, Besra GS. Cell Surf 6 100040 (2020)
  16. Computational modeling and bioinformatic analyses of functional mutations in drug target genes in Mycobacterium tuberculosis. Singh P, Jamal S, Ahmed F, Saqib N, Mehra S, Ali W, Roy D, Ehtesham NZ, Hasnain SE. Comput Struct Biotechnol J 19 2423-2446 (2021)
  17. Development of a whole-cell high-throughput phenotypic screen to identify inhibitors of mycobacterial amino acid biosynthesis. Burke C, Abrahams KA, Richardson EJ, Loman NJ, Alemparte C, Lelievre J, Besra GS. FASEB Bioadv 1 246-254 (2019)
  18. Discovery of novel reversible inhibitor of DprE1 based on benzomorpholine for the treatment of tuberculosis. Xiang W, He H, Duan X, He Z, Xu X, Liao M, Teng F, Li X, Luo T, Zeng J, Yu L, Gao C. Microbiol Spectr e0472122 (2023)
  19. Drug development: The cell wall as a drug target. Cox JA. Int J Mycobacteriol 5 Suppl 1 S156 (2016)
  20. Hit Compounds and Associated Targets in Intracellular Mycobacterium tuberculosis. Tsui CKM, Sorrentino F, Narula G, Mendoza-Losana A, Del Rio RG, Herrán EP, Lopez A, Bojang A, Zheng X, Remuiñán-Blanco MJ, Av-Gay Y. Molecules 27 4446 (2022)
  21. Lack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System. Grzegorzewicz AE, Lelièvre J, Esquivias J, Angala B, Liu J, Lee RE, McNeil MR, Jackson M. Antimicrob Agents Chemother 65 e01914-20 (2020)
  22. Ligand-protein interactions of plant-isolated (9z,12z)-octadeca-9,12-dienoic acid with Β-ketoacyl-Acp synthase (KasA) in potential anti-tubercular drug designing. Mtewa AG, Bvunzawabaya JT, Ngwira KJ, Lampiao F, Maghembe R, Okella H, Weisheit A, Tolo CU, Ogwang PE, Sesaazi DC. Sci Afr 12 e00824 (2021)
  23. Machine Learning Models for Mycobacterium tuberculosis In Vitro Activity: Prediction and Target Visualization. Lane TR, Urbina F, Rank L, Gerlach J, Riabova O, Lepioshkin A, Kazakova E, Vocat A, Tkachenko V, Cole S, Makarov V, Ekins S. Mol Pharm 19 674-689 (2022)
  24. Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure-Activity Relationship and Target Identification Studies. Wilson CR, Gessner RK, Moosa A, Seldon R, Warner DF, Mizrahi V, Soares de Melo C, Simelane SB, Nchinda A, Abay E, Taylor D, Njoroge M, Brunschwig C, Lawrence N, Boshoff HIM, Barry CE, Sirgel FA, van Helden P, Harris CJ, Gordon R, Ghidelli-Disse S, Pflaumer H, Boesche M, Drewes G, Sanz O, Santos G, Rebollo-Lopez MJ, Urones B, Selenski C, Lafuente-Monasterio MJ, Axtman M, Lelièvre J, Ballell L, Mueller R, Street LJ, Ghorpade SR, Chibale K. J. Med. Chem. 60 10118-10134 (2017)
  25. Congress On the Hunt for Next-Generation Antimicrobial Agents: An Online Symposium Organized Jointly by the French Society for Medicinal Chemistry (Société de Chimie Thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) on 9-10 December 2021. Antraygues K, Compagne N, Ruggieri F, Djaout K, Edoo Z, Eveque M, Faïon L, Gioia B, Tangara S, Vieira Da Cruz A, Villemagne B, Flipo M, Baulard A, Willand N. Pharmaceuticals (Basel) 15 388 (2022)
  26. Structural rearrangements occurring upon cofactor binding in the Mycobacterium smegmatis β-ketoacyl-acyl carrier protein reductase MabA. Küssau T, Flipo M, Van Wyk N, Viljoen A, Olieric V, Kremer L, Blaise M. Acta Crystallogr D Struct Biol 74 383-393 (2018)
  27. Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA. Kumar P, Capodagli GC, Awasthi D, Shrestha R, Maharaja K, Sukheja P, Li SG, Inoyama D, Zimmerman M, Ho Liang HP, Sarathy J, Mina M, Rasic G, Russo R, Perryman AL, Richmann T, Gupta A, Singleton E, Verma S, Husain S, Soteropoulos P, Wang Z, Morris R, Porter G, Agnihotri G, Salgame P, Ekins S, Rhee KY, Connell N, Dartois V, Neiditch MB, Freundlich JS, Alland D. MBio 9 (2018)
  28. The multi-target aspect of an MmpL3 inhibitor: The BM212 series of compounds bind EthR2, a transcriptional regulator of ethionamide activation. Moorey AR, Cabanillas A, Batt SM, Ghidelli-Disse S, Urones B, Sanz O, Lelievre J, Bantscheff M, Cox LR, Besra GS. Cell Surf 7 100068 (2021)


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