mecA

mecA is a gene found in bacterial cells which allows them to be resistant to antibiotics such as methicillin, penicillin and other penicillin-like antibiotics.[1]

The bacteria strain most commonly known to carry mecA is methicillin-resistant Staphylococcus aureus (MRSA). In Staphylococcus species, mecA is spread through the staphylococcal chromosome cassette SCCmec genetic element.[2] Resistant strains cause many hospital-acquired infections.[3]

mecA encodes the protein PBP2A (penicillin-binding protein 2A), a transpeptidase that helps form the bacterial cell wall. PBP2A has a lower affinity for beta-lactam antibiotics such as methicillin and penicillin than DD-transpeptidase 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.[4] The bacteria can then replicate as normal.

History

Methicillin resistance first emerged in hospitals in Staphylococcus aureus that was more aggressive and failed to respond to methicillin treatment.[5] 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.[5][6] 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.[7] 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.[8]

Detection

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.[9] cefoxitin disc diffusion uses phenotypic resistance to test not only for methicillin resistant strains but also for low resistant strains.[10] 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.[11] 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.[12]

Structure

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.[13] This cassette is a 52 kilobase piece of DNA that contains mecA and two recombinase genes, ccrA and ccrB.[7] 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.[14] 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.[15] 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.[16] 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.[17]

Mechanism of resistance

Penicillin, its derivatives and methicilin, 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.[18] 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.[18] 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.[19] 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.[20] 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.[21] 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.[21][20] 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.[22] 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.[23]

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.[24] 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.[25]

Evolutionary history

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.[26] 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.[27]

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.[28]

gollark: You mean abandoned mineshafts?
gollark: Very expensively, though. Maybe I should crafttweaker it.
gollark: I use kindofcheaty entropinnyum setups mostly, so yes.
gollark: Well, thanks, that's useful.
gollark: Ah, so it does, that's cool.

References
  1. Ubukata K, Nonoguchi R, Matsuhashi M, Konno M (May 1989). "Expression and inducibility in Staphylococcus aureus of the mecA gene, which encodes a methicillin-resistant S. aureus-specific penicillin-binding protein". Journal of Bacteriology. 171 (5): 2882–5. doi:10.1128/jb.171.5.2882-2885.1989. PMC 209980. PMID 2708325.
  2. Deurenberg RH, Stobberingh EE (March 2009). "The molecular evolution of hospital- and community-associated methicillin-resistant Staphylococcus aureus". Current Molecular Medicine. 9 (2): 100–15. doi:10.2174/156652409787581637. PMID 19275621.
  3. Wielders CL, Fluit AC, Brisse S, Verhoef J, Schmitz FJ (November 2002). "mecA gene is widely disseminated in Staphylococcus aureus population". Journal of Clinical Microbiology. 40 (11): 3970–5. doi:10.1128/jcm.40.11.3970-3975.2002. PMC 139644. PMID 12409360.
  4. Fogarty LR, Haack SK, Johnson HE, Brennan AK, Isaacs NM, Spencer C (2015). "Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) at ambient freshwater beaches". Journal of Water and Health. 13 (3): 680–92. doi:10.2166/wh.2014.278. PMID 26322754.
  5. Lowy FD (May 2003). "Antimicrobial resistance: the example of Staphylococcus aureus". The Journal of Clinical Investigation. 111 (9): 1265–73. doi:10.1172/JCI18535. PMC 154455. PMID 12727914.
  6. Basset P, Feil EJ, Zanetti G, Blanc DS (2011). Tibayrenc M (ed.). Genetics and Evolution of Infectious Disease. London: Elsevier. pp. 669–688. doi:10.1016/B978-0-12-384890-1.00025-X. ISBN 9780123848901.
  7. Katayama Y, Ito T, Hiramatsu K (June 2000). "A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 44 (6): 1549–55. doi:10.1128/aac.44.6.1549-1555.2000. PMC 89911. PMID 10817707.
  8. "Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics". World Health Organization. Retrieved 2017-11-28.
  9. Ubukata K, Nakagami S, Nitta A, Yamane A, Kawakami S, Sugiura M, Konno M (July 1992). "Rapid detection of the mecA gene in methicillin-resistant staphylococci by enzymatic detection of polymerase chain reaction products". Journal of Clinical Microbiology. 30 (7): 1728–33. PMC 265371. PMID 1629327.
  10. Anand KB, Agrawal P, Kumar S, Kapila K (2009). "Comparison of cefoxitin disc diffusion test, oxacillin screen agar, and PCR for mecA gene for detection of MRSA". Indian Journal of Medical Microbiology. 27 (1): 27–9. PMID 19172055.
  11. Bignardi GE, Woodford N, Chapman A, Johnson AP, Speller DC (January 1996). "Detection of the mec-A gene and phenotypic detection of resistance in Staphylococcus aureus isolates with borderline or low-level methicillinresistance". The Journal of Antimicrobial Chemotherapy. 37 (1): 53–63. doi:10.1093/jac/37.1.53. PMID 8647774.
  12. Parvez MA, Shibata H, Nakano T, Niimi S, Fujii N, Arakaki N, Higuti T (August 2008). "No relationship exists between PBP 2a amounts expressed in different MRSA strains obtained clinically and their beta-lactam MIC values". The Journal of Medical Investigation. 55 (3–4): 246–53. doi:10.2152/jmi.55.246. PMID 18797139.
  13. Hanssen AM, Ericson Sollid JU (February 2006). "SCCmec in staphylococci: genes on the move". FEMS Immunology and Medical Microbiology. 46 (1): 8–20. doi:10.1111/j.1574-695X.2005.00009.x. PMID 16420592.
  14. Hanssen AM, Sollid JU (May 2007). "Multiple staphylococcal cassette chromosomes and allelic variants of cassette chromosome recombinases in Staphylococcus aureus and coagulase-negative staphylococci from Norway". Antimicrobial Agents and Chemotherapy. 51 (5): 1671–7. doi:10.1128/AAC.00978-06. PMC 1855542. PMID 17307983.
  15. Kuwahara-Arai K, Kondo N, Hori S, Tateda-Suzuki E, Hiramatsu K (December 1996). "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". Antimicrobial Agents and Chemotherapy. 40 (12): 2680–5. doi:10.1128/AAC.40.12.2680. PMC 163603. PMID 9124822.
  16. 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". Veterinary Microbiology. 113 (1–2): 137–41. doi:10.1016/j.vetmic.2005.10.024. PMID 16298500.
  17. 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). "Whole-genome sequencing of staphylococcus haemolyticus uncovers the extreme plasticity of its genome and the evolution of human-colonizing staphylococcal species". Journal of Bacteriology. 187 (21): 7292–308. doi:10.1128/JB.187.21.7292-7308.2005. PMC 1272970. PMID 16237012.
  18. Stapleton PD, Taylor PW (2002-02-15). "Methicillin resistance in Staphylococcus aureus: mechanisms and modulation". Science Progress. 85 (Pt 1): 57–72. doi:10.3184/003685002783238870. PMC 2065735. PMID 11969119.
  19. Reed P, Veiga H, Jorge AM, Terrak M, Pinho MG (May 2011). "Monofunctional transglycosylases are not essential for Staphylococcus aureus cell wall synthesis". Journal of Bacteriology. 193 (10): 2549–56. doi:10.1128/JB.01474-10. PMC 3133172. PMID 21441517.
  20. Pinho MG, de Lencastre H, Tomasz A (September 2001). "An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci". Proceedings of the National Academy of Sciences of the United States of America. 98 (19): 10886–91. doi:10.1073/pnas.191260798. PMC 58569. PMID 11517340.
  21. Guignard B, Entenza JM, Moreillon P (October 2005). "Beta-lactams against methicillin-resistant Staphylococcus aureus". Current Opinion in Pharmacology. Anti-infectives/New technologies. 5 (5): 479–89. doi:10.1016/j.coph.2005.06.002. PMID 16095969.
  22. 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). "Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus". Chemistry & Biology. 16 (8): 837–48. doi:10.1016/j.chembiol.2009.05.012. PMID 19716474.
  23. Bernal P, Lemaire S, Pinho MG, Mobashery S, Hinds J, Taylor PW (July 2010). "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". The Journal of Biological Chemistry. 285 (31): 24055–65. doi:10.1074/jbc.M110.114793. PMC 2911331. PMID 20516078.
  24. Lee SH, Jarantow LW, Wang H, Sillaots S, Cheng H, Meredith TC, Thompson J, Roemer T (November 2011). "Antagonism of chemical genetic interaction networks resensitize MRSA to β-lactam antibiotics". Chemistry & Biology. 18 (11): 1379–89. doi:10.1016/j.chembiol.2011.08.015. PMID 22118672.
  25. Memmi G, Filipe SR, Pinho MG, Fu Z, Cheung A (November 2008). "Staphylococcus aureus PBP4 is essential for beta-lactam resistance in community-acquired methicillin-resistant strains". Antimicrobial Agents and Chemotherapy. 52 (11): 3955–66. doi:10.1128/AAC.00049-08. PMC 2573147. PMID 18725435.
  26. 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". Biochemistry. 46 (27): 8050–7. doi:10.1021/bi7004587. PMID 17567045.
  27. Severin A, Wu SW, Tabei K, Tomasz A (October 2005). "High-level (beta)-lactam resistance and cell wall synthesis catalyzed by the mecA homologue of Staphylococcus sciuri introduced into Staphylococcus aureus". Journal of Bacteriology. 187 (19): 6651–8. doi:10.1128/JB.187.19.6651-6658.2005. PMC 1251583. PMID 16166526.
  28. Tsubakishita S, Kuwahara-Arai K, Sasaki T, Hiramatsu K (October 2010). "Origin and molecular evolution of the determinant of methicillin resistance in staphylococci". Antimicrobial Agents and Chemotherapy. 54 (10): 4352–9. doi:10.1128/AAC.00356-10. PMC 2944575. PMID 20679504.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.