An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-likeproperties, and in vivo efficacy

Antimicrobial Agents and Chemotherapy

Volumn 57, Issue 1, 2013, Pages 317-325

  Stokes, Neil R ^a   Baker, Nicola ^a,d   Bennett, James M ^a   Berry, Joanne ^a   Collins, Ian ^a   Czaplewski, Lloyd G ^a,e   Logan, Alastair ^a   Macdonald, Rebecca ^a   MacLeod, Leanne ^a,f   Peasley, Hilary ^a   Mitchell, Jeffrey P ^b   Nayal, Narendra ^c   Yadav, Anju ^c   Srivastava, Anil ^c   Haydon, David J ^a  

^a Biota Europe Ltd   (United Kingdom)

^b Biota Scientific Management Pty Ltd   (Australia)

^c JUBILANT BIOSYS LTD   (India)

^d LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE   (United Kingdom)

^e Chemical Biology Ventures Limited   (United Kingdom)

^f TMO Renewables Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 METHOXYBENZAMIDE; PC 190723; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBACTERIAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BACTERIAL CELL; CELL DIVISION; CONTROLLED STUDY; CYTOKINESIS; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG INHIBITION; DRUG POTENCY; DRUG STABILITY; DRUG STRUCTURE; FEMALE; GENE MUTATION; IN VITRO STUDY; IN VIVO STUDY; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; MINIMUM INHIBITORY CONCENTRATION; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; STAPHYLOCOCCUS; STAPHYLOCOCCUS EPIDERMIDIS; STAPHYLOCOCCUS INFECTION;

ADMINISTRATION, ORAL; ANIMALS; ANTI-BACTERIAL AGENTS; BACTERIAL PROTEINS; BENZAMIDES; BIOLOGICAL AVAILABILITY; COLONY COUNT, MICROBIAL; CYTOKINESIS; CYTOSKELETAL PROTEINS; DRUG RESISTANCE, MULTIPLE, BACTERIAL; FEMALE; INJECTIONS, INTRAVENOUS; METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS; MICE; MICROBIAL SENSITIVITY TESTS; MUTATION; OXAZOLES; PRODRUGS; STAPHYLOCOCCAL INFECTIONS; STAPHYLOCOCCUS EPIDERMIDIS; SUCCINATES; SUCCINIC ACID; THIGH; TREATMENT OUTCOME;

EID: 84872020106     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.01580-12     Document Type: Article

References (46)

1. Infectious Diseases Society of America. 2004. Bad bugs, no drugs: as antibiotic discovery stagnates, a public health crisis brews. Infectious Diseases Society of America, Alexandria, VA.
2. Spellberg B, Guidos R, Gilbert D, Bradley J, Bucher HW, Scheld WM, Bartlett JG, Edwards J, Jr. 2008. The epidemic of antibiotic-resistant infections: a call to arms for the medical community from the Infectious Diseases Society of America. Clin. Infect. Dis. 46:155-164.
3. Fischbach MA, Walsh CT. 2009. Antibiotics for emerging pathogens. Science 325:1089-1093.
4. Rice LB. 2008. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect. Dis. 197:1079-1081.
5. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J. 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48:1-12.
6. Jabes D. 2011. The antibiotic R&D pipeline: an update. Curr. Opin. Microbiol. 14:564-569.
7. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. 2007. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Disc. 6:29-40.
8. Awasthi D, Kumar K, Ojima I. 2011. Therapeutic potential of FtsZ inhibition: a patent perspective. Expert Opin. Ther. Patents 21:657-679.
9. Czaplewski LG, Stokes NR, Ruston S, Haydon DJ. 2012. Antibacterial inhibitors of the essential cell division protein FtsZ, p 957-968. In Dougherty TJ, Pucci MJ (ed), Antibiotic discovery and development. Springer, New York, NY.
10. Lock RL, Harry EJ. 2008. Cell-division inhibitors: new insights for future antibiotics. Nat. Rev. Drug Disc. 7:324-338.
11. Ma S, Ma S. 2012. The development of FtsZ inhibitors as potential antibacterial agents. ChemMedChem 7:1161-1172.
12. Schaffner-Barbero C, Martín-Fontecha M, Chacón P, Andreu JM. 2012. Targeting the assembly of bacterial cell division protein FtsZ with small molecules. ACS Chem. Biol. 7:269-277.
13. Vollmer W. 2006. The prokaryotic cytoskeleton: a putative target for inhibitors and antibiotics? Appl. Microbiol. Biotechnol. 73:37-47.
14. Adams DW, Errington J. 2009. Bacterial cell division: assembly, maintenance and disassembly of the Z ring. Nat. Rev. Microbiol. 7:642-653.
15. Errington J, Daniel RA, Scheffers D-J. 2003. Cytokinesis in bacteria. Microbiol. Mol. Biol. Rev. 67:52-65.
16. Beall B, Lutkenhaus J. 1991. FtsZ in Bacillus subtilis is required for vegetative septation and for asymmetric septation during sporulation. Genes Dev. 5:447-455.
17. Dai K, Lutkenhaus J. 1991. ftsZ is an essential cell division gene in Escherichia coli. J. Bacteriol. 173:3500-3506.
18. Pinho MG, Errington J. 2003. Dispersed mode of Staphylococcus aureus cell wall synthesis in the absence of the division machinery. Mol. Microbiol. 50:871-881.
19. Downing KH. 2000. Structural basis for the interaction of tubulin with proteins and drugs that affect microtubule dynamics. Annu. Rev. Cell Dev. Biol. 16:89-111.
20. Löwe J, Amos LA. 1998. Crystal structure of the bacterial cell-division protein FtsZ. Nature 391:203-206.
21. Nogales E, Wolf SG, Downing KH. 1998. Structure of the αβ tubulin dimer by electron crystallography. Nature 391:199-203.
22. Margalit DN, Romberg L, Mets RB, Hebert AM, Mitchison TJ, Kirschner MW, RayChaudhuri D. 2004. Targeting cell division: small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethality. Proc. Natl. Acad. Sci. U. S. A. 101:11821-11826.
23. Stokes NR, Sievers J, Barker S, Bennett JM, Brown DR, Collins I, Errington VM, Foulger D, Hall M, Halsey R, Johnson H, Rose V, Thomaides HB, Haydon DJ, Czaplewski LG, Errington J. 2005. Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay. J. Biol. Chem. 280:39709-39715.
24. Wang J, Galgoci A, Kodali S, Herath KB, Jayasuriya H, Dorso K, Vicente F, González A, Cully D, Bramhill D, Singh S. 2003. Discovery of a small molecule that inhibits cell division by blocking FtsZ, a novel therapeutic target of antibiotics. J. Biol. Chem. 278:44424-44428.
25. Läppchen T, Hartog AF, Pinas VA, Koomen G-J, den Blaauwen T. 2005. GTP analogue inhibits polymerization and GTPase activity of the bacterial protein FtsZ without affecting its eukaryotic homologue tubulin. Biochemistry 44:7879-7884.
26. Paradis-Bleau C, Beaumont M, Sanschagrin F, Voyer N, Levesque RC. 2007. Parallel solid synthesis of inhibitors of the essential cell division FtsZ enzyme as a new potential class of antibacterials. Bioorg. Med. Chem. 15:1330-1340.
27. Jennings LD, Foreman KW, Rush TS, III, Tsao DH, Mosyak L, Kincaid SL, Sukhdeo MN, Sutherland AG, Ding W, Kenny CH, Sabus CL, Liu H, Dushin EG, Moghazeh SL, Labthavikul P, Petersen PJ, Tuckman M, Haney SA, Ruzin AV. 2004. Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction. Bioorg. Med. Chem. 12:5115-5131.
28. Sutherland AG, Alvarez J, Ding W, Foreman KW, Kenny CH, Labthavikul P, Mosyak L, Petersen PJ, Rush TS, III, Ruzin A, Tsao DH, Wheless KL. 2003. Structure-based design of carboxybiphenylindole inhibitors of the ZipA-FtsZ interaction. Org. Biomol. Chem. 1:4138-4140.
29. Tsao DH, Sutherland AG, Jennings LD, Li Y, Rush TS, III, Alvarez JC, Ding W, Dushin EG, Dushin RG, Haney SA, Kenny CH, Malakian AK, Nilakantan R, Mosyak L. 2006. Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design. Bioorg. Med. Chem. 14:7953-7961.
30. Haydon DJ, Stokes NR, Ure R, Galbraith G, Bennett JM, Brown DR, Baker PJ, Barynin VV, Rice DW, Sedelnikova SE, Heal JR, Sheridan JM, Aiwale ST, Chauhan PK, Srivastava A, Taneja A, Collins I, Errington J, Czaplewski LG. 2008. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321:1673-1675.
31. Adams DW, Wu LJ, Czaplewski LG, Errington J. 2011. Multiple effects of benzamide antibiotics on FtsZ function. Mol. Microbiol. 80:68-84.
32. Andreu JM, Schaffner-Barbero C, Huecas S, Alonso D, Lopez-Rodriguez ML, Ruiz-Avila LB, Núñez-Ramírez R, Llorca O, Martín-Galiano AJ. 2010. The antibacterial cell division inhibitor PC190723 is an FtsZ polymer-stabilizing agent that induces filament assembly and condensation. J. Biol. Chem. 285:14239-14246.
33. Tan CM, Therien AG, Lu J, Lee SH, Caron A, Gill CJ, Lebeau-Jacob C, Benton-Perdomo L, Monteiro JM, Pereira PM, Elsen NL, Wu J, Deschamps K, Petcu M, Wong S, Daigneault E, Kramer S, Liang L, Maxwell E, Claveau D, Vaillancourt J, Skorey K, Tam J, Wang H, Meredith TC, Sillaots S, Wang-Jarantow L, Ramtohul Y, Langlois E, Landry F, Reid JC, Parthasarathy G, Sharma S, Baryshnikova A, Lumb KJ, Pinho MG, Soisson SM, Roemer T. 2012. Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics. Sci. Transl. Med. 4:126ra35. doi:10.1126/scitranslmed.3003592.
34. Czaplewski LG, Collins I, Boyd EA, Brown D, East SP, Gardiner M, Fletcher R, Haydon DJ, Henstock V, Ingram P, Jones C, Noula C, Kennison L, Rockley C, Rose V, Thomaides-Brears HB, Ure R, Whittaker M, Stokes NR. 2009. Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ. Bioorg. Med. Chem. Lett. 19:524-527.
35. Haydon DJ, Bennett JM, Brown D, Collins I, Galbraith G, Lancett P, Macdonald R, Stokes NR, Chauhan PK, Sutariya JK, Nayal N, Srivastava A, Beanland J, Hall R, Henstock V, Noula C, Rockley C, Czaplewski L. 2010. Creating an antibacterial with in vivo efficacy: synthesis and characterization of potent inhibitors of the bacterial cell division protein FtsZ with improved pharmaceutical properties. J. Med. Chem. 53: 3927-3936.
36. Ohashi Y, Chijiiwa Y, Suzuki K, Takahashi K, Nanamiya H, Sato T, Hosoya Y, Ochi K, Kawamura F. 1999. The lethal effect of a benzamide derivative, 3-methoxybenzamide, can be suppressed by mutations within a cell division gene, ftsZ, in Bacillus subtilis. J. Bacteriol. 181:1348-1351.
37. Clinical and Laboratory Standards Institute. 2006. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard, 7th ed. CLSI document M7-A7. Clinical and Laboratory Standards Institute, Wayne, PA.
38. Pillai SK, Moellering RC, Jr, Eliopoulos GM. 2005. Antimicrobial combinations, p 365-440. In Lorian V (ed), Antibiotics in laboratory medicine. Lippincott Williams & Wilkins, Philadelphia, PA.
39. Odds FC. 2003. Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 52:1.
40. Vickers AA, O'Neill AJ, Chopra I. 2007. Emergence and maintenance of resistance to fluoroquinolones and coumarins in Staphylococcus aureus: predictions from in vitro studies. J. Antimicrob. Chemother. 60:269-273.
41. Domadia P, Swarup S, Bhunia A, Sivaraman J, Dasgupta D. 2007. Inhibition of bacterial cell division protein FtsZ by cinnamaldehyde. Biochem. Pharmacol. 74:831-840.
42. Ito H, Ura A, Oyamada Y, Tanitame A, Yoshida H, Yamada S, Wachi M, Yamagishi J. 2006. A 4-aminofurazan derivative - A189 - inhibits assembly of bacterial cell division protein FtsZ in vitro and in vivo. Microbiol. Immunol. 50:759-764.
43. Urgaonkar S, La Pierre HS, Meir I, Lund H, RayChaudhuri D, Shaw JT. 2005. Synthesis of antimicrobial natural products targeting FtsZ: (±)-dichamanetin and (±)-2‴-hydroxy-5″- benzylisouvarinol-B. Org. Lett. 7:5609-5612.
44. Silver LL. 2011. Challenges of antibacterial discovery. Clin. Microbiol. Rev. 24:71-109.
45. O'Neill AJ, Chopra I. 2004. Preclinical evaluation of novel antibacterial agents by microbiological and molecular techniques. Expert Opin. Investig. Drugs 13:1045-1063.
46. Andersson DI, Levin BR. 1999. The biological cost of antibiotic resistance. Curr. Opin. Microbiol. 2:489-493.