308:
First, for PBP2a to properly fit onto the cell wall, to continue transpeptidation, it needs the proper amino acid residues, specifically a pentaglycine residue and an amidated glutamate residue. Second, PBP2a has an effective transpeptidase activity but lacks the transglycosylation domain of PBP2,
303:
domain, but scientists thought only monofunctional enzymes catalyze transglycosylation, yet PBP2 has domains to perform both essential processes. When antibiotics enter the medium, they bind to the transpeptidation domain and inhibit PBPs from cross-linking muropeptides, therefore preventing the
126:
that was more aggressive and failed to respond to methicillin treatment. The prevalence of this strain, MRSA, continued to increase, reaching up to 60% of
British hospitals, and has spread throughout the world and beyond hospital settings. Researchers traced the source of this resistance to the
304:
formation of stable cell wall. With cooperative action, PBP2a lacks the proper receptor for the antibiotics and continues transpeptidation, preventing cell wall breakdown. The functionality of PBP2a depends on two structural factors on the cell wall of
111:
does, so it does not bind to the ringlike structure of penicillin-like antibiotics. This enables transpeptidase activity in the presence of beta-lactams, preventing them from inhibiting cell wall synthesis. The bacteria can then replicate as normal.
309:
which builds the backbone of the cell wall with polysaccharide monomers, so PBP2a must rely on PBP2 to continue this process. The latter forms a therapeutic target to improve the ability of beta-lactams to prevent cell wall synthesis in resistant
1588:
Fuda C, Suvorov M, Shi Q, Hesek D, Lee M, Mobashery S (July 2007). "Shared functional attributes between the mecA gene product of
Staphylococcus sciuri and penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus".
1119:
Cano I, Alonso MC, Garcia-Rosado E, Saint-Jean SR, Castro D, Borrego JJ (March 2006). "Detection of lymphocystis disease virus (LCDV) in asymptomatic cultured gilt-head seabream (Sparus aurata, L.) using an immunoblot technique".
1449:"Insertion of epicatechin gallate into the cytoplasmic membrane of methicillin-resistant Staphylococcus aureus disrupts penicillin-binding protein (PBP) 2a-mediated beta-lactam resistance by delocalizing PBP2"
1405:
Huber J, Donald RG, Lee SH, Jarantow LW, Salvatore MJ, Meng X, Painter R, Onishi RH, Occi J, Dorso K, Young K, Park YW, Skwish S, Szymonifka MJ, Waddell TS, Miesel L, Phillips JW, Roemer T (August 2009).
290:
antibiotics inhibits activity of the cell-wall forming penicillin-binding protein family (PBP 1, 2, 3 and 4). This disrupts the cell wall structure, causing the cytoplasm to leak and cell death. However,
313:. Identifying inhibitors of glycosylases involved in the cell wall synthesis and modulating their expression can resensitize these previously resistant bacteria to beta-lactam treatment. For example,
317:, a compound found in green tea, has shown signs of lowering the resistance to beta-lactams, to the point where oxacillin, which acts on PBP2 and PBP2a, effectively inhibits cell wall formation.
324:. These gene networks are mainly involved in cell division, and cell wall synthesis and function, where there PBP2a localizes. Furthermore, other PBP proteins also affect the resistance of
299:
depends on transglycosylation to form linear polymer of sugar monomers and transpeptidation to form an interlinking peptides to strengthen the newly developed cell wall. PBPs have a
1072:"Suppression of methicillin resistance in a mecA-containing pre-methicillin-resistant Staphylococcus aureus strain is caused by the mecI-mediated repression of PBP 2' production"
1023:"Multiple staphylococcal cassette chromosomes and allelic variants of cassette chromosome recombinases in Staphylococcus aureus and coagulase-negative staphylococci from Norway"
159:(PCR). Alternative methods include enzymatic detection PCR, which labels the PCR with enzymes detectable by immunoabsorbant assays. This takes less time and does not need gel
295:
codes for PBP2a that has a lower affinity for beta-lactams, which keeps the structural integrity of the cell wall, preventing cell death. Bacterial cell wall synthesis in
250:
strains isolated from humans either lack these regulatory elements or contain mutations in these genes that cause a loss of function of the protein products that inhibit
175:-positive strains can determine how resistant the strain is to methicillin. These phenotypic assays cannot rely on the accumulation of PBP2a, the protein product of
1157:"Whole-genome sequencing of staphylococcus haemolyticus uncovers the extreme plasticity of its genome and the evolution of human-colonizing staphylococcal species"
1626:"High-level (beta)-lactam resistance and cell wall synthesis catalyzed by the mecA homologue of Staphylococcus sciuri introduced into Staphylococcus aureus"
463:"Expression and inducibility in Staphylococcus aureus of the mecA gene, which encodes a methicillin-resistant S. aureus-specific penicillin-binding protein"
1155:
Takeuchi F, Watanabe S, Baba T, Yuzawa H, Ito T, Morimoto Y, Kuroda M, Cui L, Takahashi M, Ankai A, Baba S, Fukui S, Lee JC, Hiramatsu K (November 2005).
143:(WHO) put MRSA on their list of priority bacterial resistant pathogens and made it a high priority target for further research and treatment development.
900:"Detection of the mec-A gene and phenotypic detection of resistance in Staphylococcus aureus isolates with borderline or low-level methicillinresistance"
510:
Deurenberg RH, Stobberingh EE (March 2009). "The molecular evolution of hospital- and community-associated methicillin-resistant
Staphylococcus aureus".
1408:"Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus"
343:
is acquired and transmitted through a mobile genetic element, that inserts itself into the host genome. That structure is conserved between the
848:
66:
941:"No relationship exists between PBP 2a amounts expressed in different MRSA strains obtained clinically and their beta-lactam MIC values"
800:"Rapid detection of the mecA gene in methicillin-resistant staphylococci by enzymatic detection of polymerase chain reaction products"
218:
complex into the host genome requires the recombinases. Researchers have isolated multiple genetic variants from resistant strains of
774:
167:
uses phenotypic resistance to test not only for methicillin resistant strains but also for low resistant strains. The presence of
727:"A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus"
392:
increases. Even though the muropeptides (peptidoglycan precursors) that both species use are the same, the protein product of
1310:"An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci"
1541:"Staphylococcus aureus PBP4 is essential for beta-lactam resistance in community-acquired methicillin-resistant strains"
1370:
Guignard B, Entenza JM, Moreillon P (October 2005). "Beta-lactams against methicillin-resistant
Staphylococcus aureus".
775:"Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics"
706:
1730:
849:"Comparison of cefoxitin disc diffusion test, oxacillin screen agar, and PCR for mecA gene for detection of MRSA"
255:
1750:
87:
17:
373:. The structure of the protein product of this homologue is so similar that the protein can be used in
179:, as a test for methicillin resistance, as no connection between protein amount and resistance exists.
97:
1755:
1498:
Lee SH, Jarantow LW, Wang H, Sillaots S, Cheng H, Meredith TC, Thompson J, Roemer T (November 2011).
432:
156:
140:
195:
1258:"Monofunctional transglycosylases are not essential for Staphylococcus aureus cell wall synthesis"
104:. PBP2A has a lower affinity for beta-lactam antibiotics such as methicillin and penicillin than
596:"Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) at ambient freshwater beaches"
389:
132:
52:
1675:"Origin and molecular evolution of the determinant of methicillin resistance in staphylococci"
1500:"Antagonism of chemical genetic interaction networks resensitize MRSA to β-lactam antibiotics"
1745:
1725:
352:
223:
122:
1321:
320:
Interactions with other genes decrease resistance to beta-lactams in resistant strains of
222:, but all variants function similarly and have the same insertion site, near the host DNA
8:
314:
164:
101:
1325:
688:
1699:
1674:
1650:
1625:
1565:
1540:
1475:
1448:
1282:
1257:
1233:
1208:
1181:
1156:
1047:
1022:
698:
1096:
1071:
865:
824:
799:
798:
Ubukata K, Nakagami S, Nitta A, Yamane A, Kawakami S, Sugiura M, Konno M (July 1992).
664:
639:
571:
546:
487:
462:
1704:
1655:
1641:
1606:
1570:
1521:
1480:
1429:
1387:
1349:
1344:
1309:
1287:
1238:
1186:
1172:
1137:
1101:
1052:
1003:
998:
981:
962:
939:
Parvez MA, Shibata H, Nakano T, Niimi S, Fujii N, Arakaki N, Higuti T (August 2008).
921:
880:
829:
756:
751:
726:
702:
669:
617:
576:
562:
527:
492:
400:
can continue cell wall synthesis when a beta-lactam inhibits the PBP protein family.
300:
105:
815:
742:
478:
1694:
1686:
1645:
1637:
1598:
1560:
1552:
1516:
1511:
1499:
1470:
1460:
1424:
1419:
1407:
1379:
1339:
1329:
1277:
1269:
1228:
1220:
1176:
1168:
1129:
1091:
1083:
1042:
1034:
993:
952:
911:
870:
860:
819:
811:
746:
738:
694:
659:
651:
607:
566:
558:
519:
482:
474:
1133:
445:
contains this gene, the cassette chromosome must originate from another species.
160:
1070:
Kuwahara-Arai K, Kondo N, Hori S, Tateda-Suzuki E, Hiramatsu K (December 1996).
1383:
1314:
Proceedings of the
National Academy of Sciences of the United States of America
1224:
523:
71:
411:
complex found on the
Staphylococcal cassette chromosome, researchers used the
1739:
1465:
1447:
Bernal P, Lemaire S, Pinho MG, Mobashery S, Hinds J, Taylor PW (July 2010).
1209:"Methicillin resistance in Staphylococcus aureus: mechanisms and modulation"
1708:
1659:
1610:
1574:
1525:
1484:
1433:
1391:
1353:
1334:
1291:
1242:
1190:
1141:
1087:
1056:
1007:
966:
898:
Bignardi GE, Woodford N, Chapman A, Johnson AP, Speller DC (January 1996).
884:
760:
673:
621:
594:
Fogarty LR, Haack SK, Johnson HE, Brennan AK, Isaacs NM, Spencer C (2015).
580:
531:
1105:
925:
916:
899:
833:
496:
278:
but also for other non-essential genes the cassette chromosome can carry.
1690:
1556:
1038:
287:
198:
and insert itself into the host species, which can be any species in the
171:
alone does not determine resistant strains; further phenotypic assays of
44:
40:
1672:
1273:
612:
595:
545:
Wielders CL, Fluit AC, Brisse S, Verhoef J, Schmitz FJ (November 2002).
441:
gene on the staphylococcal cassette chromosome. Since the genome of the
1673:
Tsubakishita S, Kuwahara-Arai K, Sasaki T, Hiramatsu K (October 2010).
957:
940:
48:
1602:
875:
547:"mecA gene is widely disseminated in Staphylococcus aureus population"
655:
1069:
36:
687:
Basset P, Feil EJ, Zanetti G, Blanc DS (2011). Tibayrenc M (ed.).
1118:
332:
strains when expression of PBP4 was inhibited but PBP2a was not.
202:
genus. This cassette is a 52 kilobase piece of DNA that contains
640:"Antimicrobial resistance: the example of Staphylococcus aureus"
262:. This cassette chromosome can move between species. Two other
242:; deletions or knock-outs in these genes increase resistance of
460:
80:
1539:
Memmi G, Filipe SR, Pinho MG, Fu Z, Cheung A (November 2008).
897:
139:
present in all known MRSA strains. On
February 27, 2017, the
1446:
1256:
Reed P, Veiga H, Jorge AM, Terrak M, Pinho MG (May 2011).
1154:
797:
593:
544:
461:
Ubukata K, Nonoguchi R, Matsuhashi M, Konno M (May 1989).
151:
Successful treatment of MRSA begins with the detection of
79:
is spread through the staphylococcal chromosome cassette
1369:
938:
194:, a mobile gene element from which the gene can undergo
1497:
1307:
846:
286:
Penicillin, its derivatives and methicillin, and other
274:
show conservation in this insertion site, not only for
1404:
686:
1308:
Pinho MG, de
Lencastre H, Tomasz A (September 2001).
979:
509:
437:
the most significant candidate for the origin of the
365:
remains unknown, but they may be a precursor for the
120:
Methicillin resistance first emerged in hospitals in
1624:
Severin A, Wu SW, Tabei K, Tomasz A (October 2005).
1623:
1255:
724:
1587:
423:species. Nucleotide analysis shows the sequence of
163:, which can be costly, tedious, and unpredictable.
1538:
328:to antibiotics. Oxacillin resistance decreased in
57:The bacteria strain most commonly known to carry
1737:
230:also forms a complex with two regulatory units,
1206:
980:Hanssen AM, Ericson Sollid JU (February 2006).
847:Anand KB, Agrawal P, Kumar S, Kapila K (2009).
86:genetic element. Resistant strains cause many
27:Gene for resistance to beta-lactam antibiotics
1020:
982:"SCCmec in staphylococci: genes on the move"
725:Katayama Y, Ito T, Hiramatsu K (June 2000).
690:Genetics and Evolution of Infectious Disease
587:
39:cells which allows them to be resistant to
281:
100:2A), a transpeptidase that helps form the
1698:
1649:
1564:
1515:
1474:
1464:
1423:
1343:
1333:
1281:
1232:
1180:
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1046:
997:
956:
915:
904:The Journal of Antimicrobial Chemotherapy
874:
864:
823:
750:
663:
611:
570:
486:
190:is on staphylococcal cassette chromosome
986:FEMS Immunology and Medical Microbiology
335:
14:
1738:
1207:Stapleton PD, Taylor PW (2002-02-15).
853:Indian Journal of Medical Microbiology
693:. London: Elsevier. pp. 669–688.
385:is inserted into antibiotic sensitive
1679:Antimicrobial Agents and Chemotherapy
1545:Antimicrobial Agents and Chemotherapy
1365:
1363:
1303:
1301:
1202:
1200:
1076:Antimicrobial Agents and Chemotherapy
1027:Antimicrobial Agents and Chemotherapy
731:Antimicrobial Agents and Chemotherapy
644:The Journal of Clinical Investigation
135:, staphylococcal cassette chromosome
1374:. Anti-infectives/New technologies.
945:The Journal of Medical Investigation
720:
718:
637:
633:
631:
403:To further understand the origin of
1453:The Journal of Biological Chemistry
381:homologue of beta-lactam resistant
24:
1360:
1298:
1197:
1021:Hanssen AM, Sollid JU (May 2007).
699:10.1016/B978-0-12-384890-1.00025-X
25:
1767:
1718:
715:
628:
538:
1731:HUGO Gene Nomenclature Committee
1642:10.1128/JB.187.19.6651-6658.2005
1173:10.1128/JB.187.21.7292-7308.2005
999:10.1111/j.1574-695X.2005.00009.x
804:Journal of Clinical Microbiology
563:10.1128/jcm.40.11.3970-3975.2002
551:Journal of Clinical Microbiology
1666:
1617:
1581:
1532:
1491:
1440:
1398:
1372:Current Opinion in Pharmacology
1249:
1148:
1112:
1063:
1014:
973:
932:
891:
840:
816:10.1128/jcm.30.7.1728-1733.1992
743:10.1128/aac.44.6.1549-1555.2000
479:10.1128/jb.171.5.2882-2885.1989
357:. As of 2007, function for the
1517:10.1016/j.chembiol.2011.08.015
1425:10.1016/j.chembiol.2009.05.012
791:
767:
680:
503:
454:
347:gene product and a homologous
238:. These two genes can repress
13:
1:
866:10.1016/S0255-0857(21)01748-5
448:
1134:10.1016/j.vetmic.2005.10.024
182:
146:
88:hospital-acquired infections
53:penicillin-like antibiotics.
7:
600:Journal of Water and Health
427:is almost identical to the
206:and two recombinase genes,
96:encodes the protein PBP2A (
10:
1772:
1384:10.1016/j.coph.2005.06.002
1225:10.3184/003685002783238870
524:10.2174/156652409787581637
512:Current Molecular Medicine
434:Staphylococcus fleurettii,
256:constitutive transcription
214:. Proper insertion of the
115:
98:penicillin-binding protein
779:World Health Organization
157:polymerase chain reaction
141:World Health Organization
61:is methicillin-resistant
196:horizontal gene transfer
165:cefoxitin disc diffusion
131:gene acquired through a
1630:Journal of Bacteriology
1504:Chemistry & Biology
1466:10.1074/jbc.M110.114793
1412:Chemistry & Biology
1262:Journal of Bacteriology
1161:Journal of Bacteriology
1122:Veterinary Microbiology
467:Journal of Bacteriology
419:in comparison to other
282:Mechanism of resistance
254:. This in turn, causes
1335:10.1073/pnas.191260798
1088:10.1128/AAC.40.12.2680
390:antibiotics resistance
133:mobile genetic element
354:Staphylococcus sciuri
224:origin of replication
123:Staphylococcus aureus
63:Staphylococcus aureus
1691:10.1128/AAC.00356-10
1557:10.1128/AAC.00049-08
1039:10.1128/AAC.00978-06
638:Lowy FD (May 2003).
336:Evolutionary history
246:to methicillin. The
1751:Infectious diseases
1326:2001PNAS...9810886P
1274:10.1128/JB.01474-10
917:10.1093/jac/37.1.53
613:10.2166/wh.2014.278
431:homologue found in
407:, specifically the
315:epicatechin gallate
102:bacterial cell wall
35:is a gene found in
958:10.2152/jmi.55.246
155:, usually through
1603:10.1021/bi7004587
108:
16:(Redirected from
1763:
1756:Prokaryote genes
1713:
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1459:(31): 24055–65.
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1213:Science Progress
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1551:(11): 3955–66.
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1492:
1445:
1441:
1403:
1399:
1368:
1361:
1306:
1299:
1268:(10): 2549–56.
1254:
1250:
1219:(Pt 1): 57–72.
1205:
1198:
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1149:
1128:(1–2): 137–41.
1117:
1113:
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978:
974:
951:(3–4): 246–53.
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109:-transpeptidase
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301:transpeptidase
283:
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200:Staphylococcus
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1740:Categories
876:1807/53665
784:2017-11-28
449:References
415:gene from
387:S. aureus,
375:S. aureus.
306:S. aureus.
51:and other
49:penicillin
417:S. sciuri
398:S. sciuri
383:S. sciuri
377:When the
371:S. aureus
363:S. sciuri
330:S. aureus
326:S. aureus
322:S. aureus
311:S. aureus
297:S. aureus
266:species,
248:S. aureus
244:S. aureus
220:S. aureus
183:Structure
147:Detection
75:species,
37:bacterial
1709:20679504
1660:16166526
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1526:22118672
1485:20516078
1434:19716474
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232:mecI
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