mecA

Methicillin resistance first emerged in hospitals in Staphylococcus aureus that was more aggressive and failed to respond to methicillin treatment.{{cite journal | vauthors = Lowy FD | title = Antimicrobial resistance: the example of Staphylococcus aureus | journal = The Journal of Clinical Investigation | volume = 111 | issue = 9 | pages = 1265–73 | date = May 2003 | pmid = 12727914 | pmc = 154455 | doi = 10.1172/JCI18535 }} 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.{{cite book |doi=10.1016/B978-0-12-384890-1.00025-X | title=Genetics and Evolution of Infectious Disease|last1=Basset|first1=Patrick|last2=Feil|first2=Edward J.|last3=Zanetti|first3=Giorgio|last4=Blanc|first4=Dominique S. | name-list-style = vanc | date=2011|publisher=Elsevier|isbn=9780123848901|editor-last=Tibayrenc|editor-first=Michel|location=London|pages=669–688| url=https://serval.unil.ch/notice/serval:BIB_8173144CC9E4}} Researchers traced the source of this resistance to the mecA gene acquired through a mobile genetic element, staphylococcal cassette chromosome mec, present in all known MRSA strains.{{cite journal | vauthors = Katayama Y, Ito T, Hiramatsu K | title = A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus | journal = Antimicrobial Agents and Chemotherapy | volume = 44 | issue = 6 | pages = 1549–55 | date = June 2000 | pmid = 10817707 | pmc = 89911 | doi=10.1128/aac.44.6.1549-1555.2000}} On February 27, 2017, the World Health Organization (WHO) put MRSA on their list of priority bacterial resistant pathogens and made it a high priority target for further research and treatment development.{{cite web | url =https://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/ | title = Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics|website=World Health Organization|access-date=2017-11-28}}

Successful treatment of MRSA begins with the detection of mecA, usually through polymerase chain reaction (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 electrophoresis, which can be costly, tedious, and unpredictable.{{cite journal | vauthors = Ubukata K, Nakagami S, Nitta A, Yamane A, Kawakami S, Sugiura M, Konno M | title = Rapid detection of the mecA gene in methicillin-resistant staphylococci by enzymatic detection of polymerase chain reaction products | journal = Journal of Clinical Microbiology | volume = 30 | issue = 7 | pages = 1728–33 | date = July 1992 | doi = 10.1128/jcm.30.7.1728-1733.1992 | pmid = 1629327 | url= | pmc=265371}} cefoxitin disc diffusion uses phenotypic resistance to test not only for methicillin resistant strains but also for low resistant strains.{{cite journal | vauthors = Anand KB, Agrawal P, Kumar S, Kapila K | title = Comparison of cefoxitin disc diffusion test, oxacillin screen agar, and PCR for mecA gene for detection of MRSA | journal = Indian Journal of Medical Microbiology | volume = 27 | issue = 1 | pages = 27–9 | pmid = 19172055 | url = http://www.ijmm.org/article.asp?issn=0255-0857;year=2009;volume=27;issue=1;spage=27;epage=29;aulast=Anand | year=2009| doi = 10.1016/S0255-0857(21)01748-5 | doi-access = free | hdl = 1807/53665 | hdl-access = free }} The presence of mecA alone does not determine resistant strains; further phenotypic assays of mecA-positive strains can determine how resistant the strain is to methicillin.{{cite journal | vauthors = Bignardi GE, Woodford N, Chapman A, Johnson AP, Speller DC | title = Detection of the mec-A gene and phenotypic detection of resistance in Staphylococcus aureus isolates with borderline or low-level methicillinresistance | journal = The Journal of Antimicrobial Chemotherapy | volume = 37 | issue = 1 | pages = 53–63 | date = January 1996 | pmid = 8647774 | doi = 10.1093/jac/37.1.53 | doi-access = free }} These phenotypic assays cannot rely on the accumulation of PBP2a, the protein product of mecA, as a test for methicillin resistance, as no connection between protein amount and resistance exists.{{cite journal | vauthors = Parvez MA, Shibata H, Nakano T, Niimi S, Fujii N, Arakaki N, Higuti T | title = No relationship exists between PBP 2a amounts expressed in different MRSA strains obtained clinically and their beta-lactam MIC values | journal = The Journal of Medical Investigation | volume = 55 | issue = 3–4 | pages = 246–53 | date = August 2008 | pmid = 18797139 | doi = 10.2152/jmi.55.246 | doi-access = free }}

mecA is on staphylococcal cassette chromosome mec, a mobile gene element from which the gene can undergo horizontal gene transfer and insert itself into the host species, which can be any species in the Staphylococcus genus.{{cite journal | vauthors = Hanssen AM, Ericson Sollid JU | title = SCCmec in staphylococci: genes on the move | journal = FEMS Immunology and Medical Microbiology | volume = 46 | issue = 1 | pages = 8–20 | date = February 2006 | pmid = 16420592 | doi = 10.1111/j.1574-695X.2005.00009.x | doi-access = free }} This cassette is a 52 kilobase piece of DNA that contains mecA and two recombinase genes, ccrA and ccrB. Proper insertion of the mecA complex into the host genome requires the recombinases. Researchers have isolated multiple genetic variants from resistant strains of S. aureus, but all variants function similarly and have the same insertion site, near the host DNA origin of replication.{{cite journal | vauthors = Hanssen AM, Sollid JU | title = Multiple staphylococcal cassette chromosomes and allelic variants of cassette chromosome recombinases in Staphylococcus aureus and coagulase-negative staphylococci from Norway | journal = Antimicrobial Agents and Chemotherapy | volume = 51 | issue = 5 | pages = 1671–7 | date = May 2007 | pmid = 17307983 | doi = 10.1128/AAC.00978-06 | pmc=1855542}} mecA also forms a complex with two regulatory units, mecI and mecR1. These two genes can repress mecA; deletions or knock-outs in these genes increase resistance of S. aureus to methicillin.{{cite journal | vauthors = Kuwahara-Arai K, Kondo N, Hori S, Tateda-Suzuki E, Hiramatsu K | title = 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 | journal = Antimicrobial Agents and Chemotherapy | volume = 40 | issue = 12 | pages = 2680–5 | date = December 1996 | pmid = 9124822 | pmc=163603| doi = 10.1128/AAC.40.12.2680 }} The S. aureus 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 mecA. This in turn, causes constitutive transcription of mecA.{{cite journal | vauthors = Cano I, Alonso MC, Garcia-Rosado E, Saint-Jean SR, Castro D, Borrego JJ | title = Detection of lymphocystis disease virus (LCDV) in asymptomatic cultured gilt-head seabream (Sparus aurata, L.) using an immunoblot technique | journal = Veterinary Microbiology | volume = 113 | issue = 1–2 | pages = 137–41 | date = March 2006 | pmid = 16298500 | doi = 10.1016/j.vetmic.2005.10.024 }} This cassette chromosome can move between species. Two other Staphylococci species, S.epidermidis and S.haemolyticus, show conservation in this insertion site, not only for mecA but also for other non-essential genes the cassette chromosome can carry.{{cite journal | vauthors = 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 | title = Whole-genome sequencing of staphylococcus haemolyticus uncovers the extreme plasticity of its genome and the evolution of human-colonizing staphylococcal species | journal = Journal of Bacteriology | volume = 187 | issue = 21 | pages = 7292–308 | date = November 2005 | pmid = 16237012 | doi = 10.1128/JB.187.21.7292-7308.2005 | pmc=1272970}}

Penicillin, its derivatives and methicillin, and other beta-lactam 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.{{cite journal | vauthors = Stapleton PD, Taylor PW | title = Methicillin resistance in Staphylococcus aureus: mechanisms and modulation | journal = Science Progress | volume = 85 | issue = Pt 1 | pages = 57–72 | date = 2002-02-15 | pmid = 11969119 | doi = 10.3184/003685002783238870 | pmc=2065735}} However, mecA 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 S. aureus 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 transpeptidase domain, but scientists thought only monofunctional enzymes catalyze transglycosylation, yet PBP2 has domains to perform both essential processes.{{cite journal | vauthors = Reed P, Veiga H, Jorge AM, Terrak M, Pinho MG | title = Monofunctional transglycosylases are not essential for Staphylococcus aureus cell wall synthesis | journal = Journal of Bacteriology | volume = 193 | issue = 10 | pages = 2549–56 | date = May 2011 | pmid = 21441517 | doi = 10.1128/JB.01474-10 | pmc=3133172}} When antibiotics enter the medium, they bind to the transpeptidation domain and inhibit PBPs from cross-linking muropeptides, therefore preventing the formation of stable cell wall. With cooperative action, PBP2a lacks the proper receptor for the antibiotics and continues transpeptidation, preventing cell wall breakdown.{{cite journal | vauthors = Pinho MG, de Lencastre H, Tomasz A | title = An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 19 | pages = 10886–91 | date = September 2001 | pmid = 11517340 | doi = 10.1073/pnas.191260798 | pmc=58569| bibcode = 2001PNAS...9810886P | doi-access = free }} The functionality of PBP2a depends on two structural factors on the cell wall of S. aureus. 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.{{cite journal | vauthors = Guignard B, Entenza JM, Moreillon P | title = Beta-lactams against methicillin-resistant Staphylococcus aureus | journal = Current Opinion in Pharmacology | volume = 5 | issue = 5 | pages = 479–89 | date = October 2005 | pmid = 16095969 | doi = 10.1016/j.coph.2005.06.002 | series = Anti-infectives/New technologies }} Second, PBP2a has an effective transpeptidase activity but lacks the transglycosylation domain of PBP2, 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 S. aureus. Identifying inhibitors of glycosylases involved in the cell wall synthesis and modulating their expression can resensitize these previously resistant bacteria to beta-lactam treatment.{{cite journal | vauthors = 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 | title = Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus | journal = Chemistry & Biology | volume = 16 | issue = 8 | pages = 837–48 | date = August 2009 | pmid = 19716474 | doi = 10.1016/j.chembiol.2009.05.012 | doi-access = free }} For example, epicatechin gallate, 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.{{cite journal | vauthors = Bernal P, Lemaire S, Pinho MG, Mobashery S, Hinds J, Taylor PW | title = 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 | journal = The Journal of Biological Chemistry | volume = 285 | issue = 31 | pages = 24055–65 | date = July 2010 | pmid = 20516078 | doi = 10.1074/jbc.M110.114793 | pmc=2911331| doi-access = free }}

Interactions with other genes decrease resistance to beta-lactams in resistant strains of S. aureus. These gene networks are mainly involved in cell division, and cell wall synthesis and function, where there PBP2a localizes.{{cite journal | vauthors = Lee SH, Jarantow LW, Wang H, Sillaots S, Cheng H, Meredith TC, Thompson J, Roemer T | title = Antagonism of chemical genetic interaction networks resensitize MRSA to β-lactam antibiotics | journal = Chemistry & Biology | volume = 18 | issue = 11 | pages = 1379–89 | date = November 2011 | pmid = 22118672 | doi = 10.1016/j.chembiol.2011.08.015 | doi-access = free }} Furthermore, other PBP proteins also affect the resistance of S. aureus to antibiotics. Oxacillin resistance decreased in S. aureus strains when expression of PBP4 was inhibited but PBP2a was not.{{cite journal | vauthors = Memmi G, Filipe SR, Pinho MG, Fu Z, Cheung A | title = Staphylococcus aureus PBP4 is essential for beta-lactam resistance in community-acquired methicillin-resistant strains | journal = Antimicrobial Agents and Chemotherapy | volume = 52 | issue = 11 | pages = 3955–66 | date = November 2008 | pmid = 18725435 | doi = 10.1128/AAC.00049-08 | pmc=2573147}}

mecA is acquired and transmitted through a mobile genetic element, that inserts itself into the host genome. That structure is conserved between the mecA gene product and a homologous mecA gene product in Staphylococcus sciuri. As of 2007, function for the mecA homologue in S. sciuri remains unknown, but they may be a precursor for the mecA gene found in S. aureus.{{cite journal | vauthors = Fuda C, Suvorov M, Shi Q, Hesek D, Lee M, Mobashery S | title = Shared functional attributes between the mecA gene product of Staphylococcus sciuri and penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus | journal = Biochemistry | volume = 46 | issue = 27 | pages = 8050–7 | date = July 2007 | pmid = 17567045 | doi = 10.1021/bi7004587 }} The structure of the protein product of this homologue is so similar that the protein can be used in S. aureus. When the mecA homologue of beta-lactam resistant S. sciuri is inserted into antibiotic sensitive S. aureus, antibiotics resistance increases. Even though the muropeptides (peptidoglycan precursors) that both species use are the same, the protein product of mecA gene of the S. sciuri can continue cell wall synthesis when a beta-lactam inhibits the PBP protein family.{{cite journal | vauthors = Severin A, Wu SW, Tabei K, Tomasz A | title = High-level (beta)-lactam resistance and cell wall synthesis catalyzed by the mecA homologue of Staphylococcus sciuri introduced into Staphylococcus aureus | journal = Journal of Bacteriology | volume = 187 | issue = 19 | pages = 6651–8 | date = October 2005 | pmid = 16166526 | doi = 10.1128/JB.187.19.6651-6658.2005 | pmc=1251583}}

To further understand the origin of mecA, specifically the mecA complex found on the Staphylococcal cassette chromosome, researchers used the mecA gene from S. sciuri in comparison to other Staphylococci species. Nucleotide analysis shows the sequence of mecA is almost identical to the mecA homologue found in Staphylococcus fleurettii, the most significant candidate for the origin of the mecA gene on the staphylococcal cassette chromosome. Since the genome of the S. fleurettii contains this gene, the cassette chromosome must originate from another species.{{cite journal | vauthors = Tsubakishita S, Kuwahara-Arai K, Sasaki T, Hiramatsu K | title = Origin and molecular evolution of the determinant of methicillin resistance in staphylococci | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 10 | pages = 4352–9 | date = October 2010 | pmid = 20679504 | doi = 10.1128/AAC.00356-10 | pmc=2944575}}

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• {{Gene|mecA}} at HUGO Gene Nomenclature Committee

Category:Cell biology

Category:Infectious diseases

Category:Prokaryote genes