283:
759:
24:
608:-acetylglucosamine; this is the first enzyme described in which the substrate is present in both the catalytic and allosteric sites. Because epimerox targets the allosteric site of the bacterial 2-epimerase, low human toxicity is expected since the human 2-epimerase does not have this site.
975:
639:
to the compound (resistance frequency of <10). Thus, epimerox is an antibiotic with low resistance potential. Therefore, 2-epimerase is a new antibiotic target to which resistance is a rare event. 2-Epimerase was discovered as a target because it was one of the enzymes in the
848:
Schuch, R.; Pelzek, A. J.; Raz, A.; Euler, C. W.; Ryan, P. A.; Winer, B. Y.; Farnsworth, A.; Bhaskaran, S. S.; Stebbins, C. E.; Xu, Y.; Clifford, A.; Bearss, D. J.; Vankayalapati, H.; Goldberg, A. R.; Fischetti, V. A. (2013). Aziz, Ramy K (ed.).
698:
receptor to function, the enzymes have evolved over a billion years to identify substrate receptors in the bacterial cell wall that the bacteria cannot change easily. These substrates are either part of the
690:. For bacteriophage to survive they need to replicate inside a bacterial cell and release their progeny phage when they are assembled using their lysin. Since lysins from bacteriophage that infect
72:
331:
160:
InChI=1S/C23H16Cl2N2O4S/c24-16-8-6-14(11-17(16)25)20-9-7-15(31-20)12-18-21(28)27(23(32)26-18)19(22(29)30)10-13-4-2-1-3-5-13/h1-9,11-12,19H,10H2,(H,26,32)(H,29,30)/b18-12+
1021:
715:
Epimerox is the name of two chemically closely related compounds that were found to block 2-epimerase and act as antibiotics by the described mechanism. Both are thio
419:
InChI=1S/C23H17BrN2O3S2/c24-16-8-6-15(7-9-16)20-11-10-17(31-20)13-18-21(27)26(23(30)25-18)19(22(28)29)12-14-4-2-1-3-5-14/h1-11,13,19H,12H2,(H,25,30)(H,28,29)/b18-13+
435:
176:
622:
553:
410:
151:
809:
522:
263:
960:
577:
538:
589:
1026:
770:
763:
778:
1031:
48:)-2-(4-((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid
307:)-2-(4-((5-(3-bromophenyl)thiophene-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid
542:
351:
92:
636:
546:
295:
36:
862:
686:
enzyme called PlyG, which is produced by the Îł-bacteriophage to release its progeny from infected
613:
600:. Bacterial 2-epimerase differs from its human counterpart in that the bacterial molecule has an
976:"The structure of the major cell wall polysaccharide of Bacillus anthracis is species-specific"
827:
997:
942:
890:
371:
112:
913:"A structural basis for the allosteric regulation of non-hydrolysing UDP-GlcNAc 2-epimerases"
987:
932:
924:
880:
870:
604:
site. For enzymatic activity, the allosteric site needs to be occupied by the substrate UDP-
458:
199:
866:
937:
912:
885:
851:"Use of a Bacteriophage Lysin to Identify a Novel Target for Antimicrobial Development"
850:
645:
516:
257:
1015:
723:
700:
691:
680:
629:
396:
137:
641:
758:
282:
875:
974:
Choudhury, B; Leoff C; Saile E; Wilkins P; Quinn CP; et al. (22 Sep 2006).
720:
601:
501:
362:
242:
103:
928:
716:
695:
657:
561:
549:. It is a small molecule inhibitor compound that blocks the activity of the
23:
1001:
992:
946:
894:
726:. They differ in the residue on the thiohydantoin's carbon atom, which is (
911:
Velloso, L.M.; Bhaskaran SS; Schuch R; Fischetti VA; Stebbins CE. (2008).
774:
810:"A New Era: The Fight Against Antibiotic-Resistant Pathogenic Bacteria"
668:
653:
618:
383:
124:
664:
550:
342:
83:
515:
Except where otherwise noted, data are given for materials in their
256:
Except where otherwise noted, data are given for materials in their
757:
683:
611:
Although epimerox was originally developed specifically to target
330:
320:
71:
61:
703:
or sugars linked to it. Deletion of both 2-epimerase genes in
184:
Clc1ccc(cc1Cl)-c(cc4)oc4\C=C(/C2=O)\NC(=S)N2C(C(O)=O)Cc3ccccc3
675:
Ac at a 3:2:1 ratio). This polysaccharide is only found in
443:
Brc4ccc(cc4)-c2ccc(s2)\C=C(/C1=O)\NC(=S)N1C(C(=O)O)Cc3ccccc3
773:
of a thiohydantoin–phenylalanine imine with different
828:"New Anthrax-Killing Antibiotic Also Eliminates MRSA"
812:. New York Academy of Sciences. December 21, 2011.
621:, it was found that it is also effective against
843:
841:
839:
837:
395:
136:
541:compound being developed by scientists at the
644:pathway for synthesizing an essential neutral
821:
819:
8:
762:The last step of the epimerox synthesis, a
635:No bacteria could be identified that were
370:
274:
111:
15:
991:
936:
906:
904:
884:
874:
963:. Bioscience Technology. April 12, 2013.
1022:Protein synthesis inhibitor antibiotics
801:
440:
415:
181:
156:
422:Key: FVHHZLXFIYKOPG-QGOAFFKASA-N
350:
163:Key: CZUADNIMRCRNSB-LDADJPATSA-N
91:
7:
738:-2-ylmethylene in one compound and (
961:"MRSA-killing Antibiotic Developed"
386:
127:
826:Michael Manning (April 14, 2013).
769:The substances are prepared via a
14:
479:
470:
281:
223:
217:
211:
22:
788:. The active compounds are the
519:(at 25 °C , 100 kPa).
476:
260:(at 25 °C , 100 kPa).
558:-acetylglucosamine 2-epimerase
491:
485:
464:
235:
229:
205:
1:
750:-2-ylmethylene in the other.
876:10.1371/journal.pone.0060754
777:, which yields a mixture of
707:is lethal to the bacterium.
617:, the bacterium that causes
1048:
679:and is the receptor for a
539:broad-spectrum antibiotic
513:
451:
431:
406:
312:
294:
289:
280:
254:
192:
172:
147:
53:
35:
30:
21:
929:10.1038/sj.embor.7401154
771:Knoevenagel condensation
764:Knoevenagel condensation
694:bacteria must bind to a
628:(MRSA), and many other
993:10.1074/jbc.M605768200
766:
623:methicillin-resistant
564:enzyme that is called
543:Rockefeller University
761:
625:Staphylococcus aureus
576:2-Epimerase converts
547:Astex Pharmaceuticals
648:in the cell wall of
986:(38): 27932–27941.
867:2013PLoSO...860754S
719:derivatives of the
572:Mechanism of action
537:is an experimental
509: g·mol
277:
250: g·mol
18:
767:
614:Bacillus anthracis
523:Infobox references
275:
264:Infobox references
16:
597:
585:
531:Chemical compound
529:
528:
332:Interactive image
272:Chemical compound
270:
269:
73:Interactive image
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459:Chemical formula
399:
388:
374:
354:
334:
285:
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249:
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225:
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207:
200:Chemical formula
140:
129:
115:
95:
75:
26:
19:
1047:
1046:
1042:
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1038:
1037:
1036:
1027:Organochlorides
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1032:Organobromides
1029:
1024:
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1007:
966:
952:
923:(2): 199–205.
900:
833:
815:
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799:
797:
794:
755:
752:
712:
709:
646:polysaccharide
573:
570:
530:
527:
526:
521:
517:standard state
514:
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980:J. Biol. Chem
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861:(4): e60754.
860:
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829:
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811:
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781:
776:
772:
765:
760:
753:
751:
749:
745:
741:
737:
733:
729:
725:
724:phenylalanine
722:
718:
710:
708:
706:
702:
701:peptidoglycan
697:
693:
692:Gram-positive
689:
685:
682:
681:bacteriophage
678:
674:
670:
666:
663:
659:
655:
651:
647:
643:
638:
633:
631:
630:Gram-positive
627:
626:
620:
616:
615:
609:
607:
603:
599:
593:
587:
581:
571:
569:
567:
563:
559:
557:
552:
548:
544:
540:
536:
524:
518:
512:
505:
503:
500:
499:
463:
460:
456:
455:
450:
441:
437:
430:
416:
412:
405:
398:
394:
393:
391:
385:
381:
380:
373:
369:
368:
366:
364:
361:
360:
353:
352:ChEMBL3099318
349:
348:
346:
344:
341:
340:
333:
329:
328:
326:
322:
317:
316:
311:
306:
302:
297:
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279:
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110:
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107:
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102:
101:
94:
93:ChEMBL3099046
90:
89:
87:
85:
82:
81:
74:
70:
69:
67:
63:
58:
57:
52:
47:
43:
38:
34:
29:
25:
20:
983:
979:
969:
955:
920:
916:
858:
854:
804:
789:
783:
779:
768:
747:
743:
739:
735:
731:
727:
714:
705:B. anthracis
704:
688:B. anthracis
687:
677:B. anthracis
676:
672:
661:
650:B. anthracis
649:
642:biosynthetic
634:
624:
612:
610:
605:
598:-mannosamine
591:
586:-glucosamine
579:
575:
565:
555:
534:
533:
313:Identifiers
304:
300:
54:Identifiers
45:
41:
568:for short.
566:2-epimerase
452:Properties
193:Properties
1016:Categories
796:References
721:amino acid
632:bacteria.
602:allosteric
502:Molar mass
363:ChemSpider
319:3D model (
296:IUPAC name
243:Molar mass
104:ChemSpider
60:3D model (
37:IUPAC name
775:aldehydes
754:Synthesis
748:thiophene
730:)-5-(3,4-
717:hydantoin
711:Chemistry
696:cell wall
637:resistant
562:epimerase
276:Epimerox
17:Epimerox
1002:16870610
947:18188181
917:EMBO Rep
895:23593301
855:PLOS ONE
732:dichloro
594:-acetyl-
582:-acetyl-
535:Epimerox
397:57994051
372:31124510
138:57994048
113:31128636
938:2246411
886:3622686
863:Bibcode
792:forms.
786:isomers
746:phenyl)
742:)-5-(3-
734:phenyl)
619:anthrax
384:PubChem
125:PubChem
1000:
945:
935:
893:
883:
551:enzyme
507:513.42
436:SMILES
343:ChEMBL
290:Names
248:487.35
177:SMILES
84:ChEMBL
31:Names
744:bromo
736:furan
684:lysin
560:, an
411:InChI
321:JSmol
152:InChI
62:JSmol
998:PMID
943:PMID
891:PMID
782:and
590:UDP-
578:UDP-
554:UDP-
545:and
988:doi
984:281
933:PMC
925:doi
881:PMC
871:doi
669:Man
658:Gal
654:Glu
588:to
387:CID
128:CID
1018::
996:.
982:.
978:.
941:.
931:.
919:.
915:.
903:^
889:.
879:.
869:.
857:.
853:.
836:^
818:^
665:Ac
477:Br
474:17
468:23
218:Cl
215:16
209:23
1004:.
990::
949:.
927::
921:9
897:.
873::
865::
859:8
830:.
790:E
784:Z
780:E
740:E
728:E
673:N
671:-
667::
662:N
660:-
656::
652:(
606:N
596:D
592:N
584:D
580:N
556:N
495:2
492:S
489:3
486:O
483:2
480:N
471:H
465:C
323:)
305:E
303:,
301:S
299:(
236:S
233:4
230:O
227:2
224:N
221:2
212:H
206:C
64:)
46:E
44:,
42:S
40:(
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