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Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections.

Montgomery JI, Brown MF, Reilly U, Price LM, Abramite JA, Arcari J, Barham R, Che Y, Chen JM, Chung SW, Collantes EM, Desbonnet C, Doroski M, Doty J, Engtrakul JJ, Harris TM, Huband M, Knafels JD, Leach KL, Liu S, Marfat A, McAllister L, McElroy E, Menard CA, Mitton-Fry M, Mullins L, Noe MC, O'Donnell J, Oliver R, Penzien J, Plummer M, Shanmugasundaram V, Thoma C, Tomaras AP, Uccello DP, Vaz A, Wishka DG
J Med Chem 55 1662-70 (2012)
Cited: 40 times
EuropePMC logo PMID: 22257165

Abstract

The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.

Articles - 3uhm mentioned but not cited (3)

  1. Structure of the bacterial deacetylase LpxC bound to the nucleotide reaction product reveals mechanisms of oxyanion stabilization and proton transfer. Clayton GM, Klein DJ, Rickert KW, Patel SB, Kornienko M, Zugay-Murphy J, Reid JC, Tummala S, Sharma S, Singh SB, Miesel L, Lumb KJ, Soisson SM. J Biol Chem 288 34073-34080 (2013)
  2. 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation of Pseudomonas aeruginosa LpxC Inhibitors. Zuo K, Liang L, Du W, Sun X, Liu W, Gou X, Wan H, Hu J. Int J Mol Sci 18 E761 (2017)
  3. Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors. Basak S, Li Y, Tao S, Daryaee F, Merino J, Gu C, Delker SL, Phan JN, Edwards TE, Walker SG, Tonge PJ. J Med Chem 65 11854-11875 (2022)


Reviews citing this publication (10)

  1. Targeting Metalloenzymes for Therapeutic Intervention. Chen AY, Adamek RN, Dick BL, Credille CV, Morrison CN, Cohen SM. Chem Rev 119 1323-1455 (2019)
  2. Using bacterial genomes and essential genes for the development of new antibiotics. Fields FR, Lee SW, McConnell MJ. Biochem Pharmacol 134 74-86 (2017)
  3. Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC. Erwin AL. Cold Spring Harb Perspect Med 6 a025304 (2016)
  4. LpxC inhibitors: a patent review (2010-2016). Kalinin DV, Holl R. Expert Opin Ther Pat 27 1227-1250 (2017)
  5. Structure, inhibition, and regulation of essential lipid A enzymes. Zhou P, Zhao J. Biochim Biophys Acta Mol Cell Biol Lipids 1862 1424-1438 (2017)
  6. Drug discovery strategies to outer membrane targets in Gram-negative pathogens. Brown DG. Bioorg Med Chem 24 6320-6331 (2016)
  7. Translational deficiencies in antibacterial discovery and new screening paradigms. Dunman PM, Tomaras AP. Curr Opin Microbiol 27 108-113 (2015)
  8. New molecules and adjuvants in the treatment of infections by Acinetobacter baumannii. Smani Y, Pachón-Ibáñez ME, Pachón J. Expert Opin Pharmacother 17 1207-1214 (2016)
  9. Chemical genetic approaches for the discovery of bacterial cell wall inhibitors. Gupta R, Singh M, Pathania R. RSC Med Chem 14 2125-2154 (2023)
  10. Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance. Romano KP, Hung DT. Biochim Biophys Acta Mol Cell Res 1870 119407 (2023)

Articles citing this publication (27)

  1. Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. Lin L, Tan B, Pantapalangkoor P, Ho T, Baquir B, Tomaras A, Montgomery JI, Reilly U, Barbacci EG, Hujer K, Bonomo RA, Fernandez L, Hancock RE, Adams MD, French SW, Buslon VS, Spellberg B. mBio 3 e00312-12 (2012)
  2. Translating slow-binding inhibition kinetics into cellular and in vivo effects. Walkup GK, You Z, Ross PL, Allen EK, Daryaee F, Hale MR, O'Donnell J, Ehmann DE, Schuck VJ, Buurman ET, Choy AL, Hajec L, Murphy-Benenato K, Marone V, Patey SA, Grosser LA, Johnstone M, Walker SG, Tonge PJ, Fisher SL. Nat Chem Biol 11 416-423 (2015)
  3. Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay. Nayar AS, Dougherty TJ, Ferguson KE, Granger BA, McWilliams L, Stacey C, Leach LJ, Narita S, Tokuda H, Miller AA, Brown DG, McLeod SM. J Bacteriol 197 1726-1734 (2015)
  4. Characterization of an Acinetobacter baumannii lptD Deletion Strain: Permeability Defects and Response to Inhibition of Lipopolysaccharide and Fatty Acid Biosynthesis. Bojkovic J, Richie DL, Six DA, Rath CM, Sawyer WS, Hu Q, Dean CR. J Bacteriol 198 731-741 (2015)
  5. Cell-based screen for discovering lipopolysaccharide biogenesis inhibitors. Zhang G, Baidin V, Pahil KS, Moison E, Tomasek D, Ramadoss NS, Chatterjee AK, McNamara CW, Young TS, Schultz PG, Meredith TC, Kahne D. Proc Natl Acad Sci U S A 115 6834-6839 (2018)
  6. LpxC inhibitors as new antibacterial agents and tools for studying regulation of lipid A biosynthesis in Gram-negative pathogens. Tomaras AP, McPherson CJ, Kuhn M, Carifa A, Mullins L, George D, Desbonnet C, Eidem TM, Montgomery JI, Brown MF, Reilly U, Miller AA, O'Donnell JP. mBio 5 e01551-14 (2014)
  7. Mutants resistant to LpxC inhibitors by rebalancing cellular homeostasis. Zeng D, Zhao J, Chung HS, Guan Z, Raetz CR, Zhou P. J Biol Chem 288 5475-5486 (2013)
  8. Inhibition of LpxC Increases Antibiotic Susceptibility in Acinetobacter baumannii. García-Quintanilla M, Caro-Vega JM, Pulido MR, Moreno-Martínez P, Pachón J, McConnell MJ. Antimicrob Agents Chemother 60 5076-5079 (2016)
  9. Structural basis of the promiscuous inhibitor susceptibility of Escherichia coli LpxC. Lee CJ, Liang X, Gopalaswamy R, Najeeb J, Ark ED, Toone EJ, Zhou P. ACS Chem Biol 9 237-246 (2014)
  10. Toxic Accumulation of LPS Pathway Intermediates Underlies the Requirement of LpxH for Growth of Acinetobacter baumannii ATCC 19606. Richie DL, Takeoka KT, Bojkovic J, Metzger LE, Rath CM, Sawyer WS, Wei JR, Dean CR. PLoS One 11 e0160918 (2016)
  11. Interplay of Klebsiella pneumoniae fabZ and lpxC Mutations Leads to LpxC Inhibitor-Dependent Growth Resulting from Loss of Membrane Homeostasis. Mostafavi M, Wang L, Xie L, Takeoka KT, Richie DL, Casey F, Ruzin A, Sawyer WS, Rath CM, Wei JR, Dean CR. mSphere 3 e00508-18 (2018)
  12. LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents. Kurasaki H, Tsuda K, Shinoyama M, Takaya N, Yamaguchi Y, Kishii R, Iwase K, Ando N, Nomura M, Kohno Y. ACS Med Chem Lett 7 623-628 (2016)
  13. A Fluorescent Probe Distinguishes between Inhibition of Early and Late Steps of Lipopolysaccharide Biogenesis in Whole Cells. Moison E, Xie R, Zhang G, Lebar MD, Meredith TC, Kahne D. ACS Chem Biol 12 928-932 (2017)
  14. Crystal structure of lipid A disaccharide synthase LpxB from Escherichia coli. Bohl HO, Shi K, Lee JK, Aihara H. Nat Commun 9 377 (2018)
  15. Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Revealed LpxC as a Potential Drug Target Against Multi-Drug Resistant Klebsiella pneumoniae. Ahmad S, Navid A, Akhtar AS, Azam SS, Wadood A, Pérez-Sánchez H. Interdiscip Sci 11 508-526 (2019)
  16. Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors. Murphy-Benenato KE, Olivier N, Choy A, Ross PL, Miller MD, Thresher J, Gao N, Hale MR. ACS Med Chem Lett 5 1213-1218 (2014)
  17. Synthesis, biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors. Szermerski M, Melesina J, Wichapong K, Löppenberg M, Jose J, Sippl W, Holl R. Bioorg Med Chem 22 1016-1028 (2014)
  18. Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics. Cho J, Lee M, Cochrane CS, Webster CG, Fenton BA, Zhao J, Hong J, Zhou P. Proc Natl Acad Sci U S A 117 4109-4116 (2020)
  19. Structure-based discovery of LpxC inhibitors. Zhang J, Chan A, Lippa B, Cross JB, Liu C, Yin N, Romero JA, Lawrence J, Heney R, Herradura P, Goss J, Clark C, Abel C, Zhang Y, Poutsiaka KM, Epie F, Conrad M, Mahamoon A, Nguyen K, Chavan A, Clark E, Li TC, Cheng RK, Wood M, Andersen OA, Brooks M, Kwong J, Barker J, Parr IB, Gu Y, Ryan MD, Coleman S, Metcalf CA. Bioorg Med Chem Lett 27 1670-1680 (2017)
  20. Generation of a novel nucleic acid-based reporter system to detect phenotypic susceptibility to antibiotics in Mycobacterium tuberculosis. Mulvey MC, Sacksteder KA, Einck L, Nacy CA. mBio 3 e00312-11 (2012)
  21. Prey Range and Genome Evolution of Halobacteriovorax marinus Predatory Bacteria from an Estuary. Enos BG, Anthony MK, DeGiorgis JA, Williams LE. mSphere 3 e00508-17 (2018)
  22. Targeting Mobilization of Ferrous Iron in Pseudomonas aeruginosa Infection with an Iron(II)-Caged LpxC Inhibitor. Blank BR, Talukder P, Muir RK, Green ER, Skaar EP, Renslo AR. ACS Infect Dis 5 1366-1375 (2019)
  23. Crystal structure of A. aeolicus LpxC with bound product suggests alternate deacetylation mechanism. Miller MD, Gao N, Ross PL, Olivier NB. Proteins 83 1706-1719 (2015)
  24. Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity. Basu R, Wang N, Basak S, Daryaee F, Babar M, Allen EK, Walker SG, Haley JD, Tonge PJ. ACS Infect Dis 7 2755-2763 (2021)
  25. Diversity-oriented functionalization of 2-pyridones and uracils. Shang Y, Wu C, Gao Q, Liu C, Li L, Zhang X, Cheng HG, Liu S, Zhou Q. Nat Commun 12 2988 (2021)
  26. Inhibition of LpxC Increases the Activity of Iron Chelators and Gallium Nitrate in Multidrug-Resistant Acinetobacter baumannii. Vinuesa V, Cruces R, Nonnoi F, McConnell MJ. Antibiotics (Basel) 10 609 (2021)
  27. Single-molecule dynamics show a transient lipopolysaccharide transport bridge. Törk L, Moffatt CB, Bernhardt TG, Garner EC, Kahne D. Nature 623 814-819 (2023)


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