βラクタマーゼ阻害薬、βラクタマーゼ阻害剤、ラクタマーゼ阻害薬

WordNet

to remain unmolested, undisturbed, or uninterrupted -- used only in infinitive form; "let her be"
work in a specific place, with a specific subject, or in a specific function; "He is a herpetologist"; "She is our resident philosopher" (同)follow
have life, be alive; "Our great leader is no more"; "My grandfather lived until the end of war" (同)live
be identical to; be someone or something; "The president of the company is John Smith"; "This is my house"
happen, occur, take place; "I lost my wallet; this was during the visit to my parents house"; "There were two hundred people at his funeral"; "There was a lot of noise in the kitchen"
have the quality of being; (copula, used with an adjective or a predicate noun); "John is rich"; "This is not a good answer"
occupy a certain position or area; be somewhere; "Where is my umbrella?" "The toolshed is in the back"; "What is behind this behavior?"
spend or use time; "I may be an hour"
limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
limit the range or extent of; "Contact between the young was inhibited by strict social customs"
stake on the outcome of an issue; "I bet $100 on that new horse"; "She played all her money on the dark horse" (同)wager, play
the act of gambling; "he did it on a bet" (同)wager
maintain with or as if with a bet; "I bet she will be there!" (同)wager
second in order of importance; "the candidate, considered a beta male, was perceived to be unable to lead his party to victory"
the 2nd letter of the Greek alphabet
preliminary or testing stage of a software or hardware product; "a beta version"; "beta software"
a substance that retards or stops an activity

PrepTutorEJDIC

《連結語として補語を伴なって…『である』,…だ,…です / 《位置・場所を表す語句を伴って》(…に)『ある』,いる(occupy a place or situation) / 〈物事が〉『存在する』,ある(exist);〈生物が〉生存する,生きている(live) / 行われる,起こる,発生する(take place, occur) / 存続する,そのままでいる(remain as before) / 《『be to』 do》 / …する予定である,…することになっている / …すべきだ / 《受動態の不定詞を伴って》…できる / 《命令》…するのだ / 《条件節に》…する意図がある / 《『if…were to』 do》…するとしたなら / 《『be』 do『ing』》《進行形》 / 《進行中の動作》…している,しつつある / 《近い未来》…しようとしている,するつもり / 《動作の反復》(いつも)…している / 《『be』+『他動詞の過去分詞』》《受動態》…される,されている / 《『be』+『自動詞の過去分詞』》《完了形》…した[状態にある]
〈感情・欲望・行動・作用など〉‘を'抑制する / (…しないように)〈人〉‘を'抑制する,妨げる《+『名』+『from』+『名』(do『ing』)》
『かけ』・(…との)かけ《+『with』+『名』》 / かけた物(金) / かけの対象 / 〈金・物〉'を'『かける』 / (かけ事・ゲームなどで)〈人〉‘と'『かけをする』《+『名』〈人〉+『on』+『名』》 / (…に)『かける』《+『on』(『against』)+『名』(one's do『ing』)》
ベータ(ギリシア語アルファベットの第2文字;B,β;英語のB,b に遭当)
抑制する人(物) / 化学反応抑制剤

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/11/18 10:23:31」(JST)

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[Wiki en表示]

Clavulanic acid

Sulbactam

Tazobactam

Avibactam

Beta lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin-like antibiotics to work. Strategies for combatting this form of resistance have included the development of new beta lactam antibiotics that are more resistant to cleavage, and the development of beta lactamase inhibitors.^[1] Although β-lactamase inhibitors have little antibiotic activity of their own,^[2] they prevent bacterial degradation of beta lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

Medical uses

The most important use of beta lactamase inhibitors is in the treatment of infections known or believed to be caused by Gram-(-) bacteria, as beta lactamase production is an important contributor to beta lactam resistance in these pathogens. In contrast, most beta lactam resistance in Gram-(+) bacteria is due variations in penicillin-binding proteins that lead to reduced binding to the beta lactam.^[3]^[4] The Gram-(+) pathogen Staphylococcus aureus produces beta lactamases, but beta lactamase inhibitors play a lesser role in treatment of these infections because the most resistant strains (methicillin-resistant Staphylococcus aureus) also use variant penicillin-binding proteins.^[5]^[6]

Mechanism of action

The Ambler classification system groups known beta lactamase enzymes into four groups according to sequence homology and presumed phylogenetic relationships. Classes A, C and D cleave beta lactams by a multi-step mechanism analogous to the mechanism of serine proteases. Upon binding, a serine hydroxyl group in the beta lactamase active site forms a transient covalent bond to the beta lactam ring carbonyl group, cleaving the beta lactam ring in the process. In a second step, nucleophilic attack by a water molecule cleaves the covalent bond between the enzyme and the carbonyl group of the erstwhile beta lactam. This allows the degraded beta lactam to diffuse away and frees up the enzyme to process additional beta lactam molecules.

Currently available beta lactamase inhibitors are effective against Ambler Class A beta lactamases (tazobactam, clavulanate, and sulbactam) or against Ambler Class A, C and some Class D beta lactamases (avibactam). Like beta lactam antibiotics, they are processed by beta lactamases to form an initial covalent intermediate. Unlike the case of beta lactam antibiotics, the formed covalent intermediate is very stable. The persistence of the covalent bond between the beta lactamase inhibitor and the beta lactamase binding site deactivates the enzyme and prevents processing of beta lactam antibiotics.^[7]

Ambler Class B beta lactams cleave beta lactams by a mechanism similar to that of metalloproteases. As no covalent intermediate is formed, the mechanism of action of marketed beta lactamase inhibitors is not applicable. Thus the spread of bacterial strains expressing metallo beta lactamases such as the New Delhi metallo-beta-lactamase 1 has engendered considerable concern.^[8]

Commonly used agents

Currently marketed beta lactamase inhibitors are not sold as individual drugs. Instead they are co-formulated with a a beta lactam that has a similar serum half-life. This is done not only for dosing convenience, but also to minimize resistance development that might occur as a result of varying exposure to one or the other drug. The main classes of beta lactam antibiotics used to treat Gram-(-) bacterial infections include (in approximate order of intrinsic resistance to cleavage by beta lactamases) penicillins (especially aminopenicillins and ureidopenicillins), 3rd generation cephalosporins, and carbapenems. Individual beta lactamase variants may target one or many of these drug classes, and only a subset will be inhibited by a given beta lactamase inhibitor.^[9] Beta lactamase inhibitors expand the useful spectrum of these beta lactam antibiotics by inhibiting the beta lactamase enzymes produced by bacteria to deactivate them.^[10]

Clavulanic acid or clavulanate, usually combined with amoxicillin (Augmentin) or ticarcillin (Timentin)
Sulbactam, usually combined with ampicillin (Unasyn) or Cefoperazone (Sulperazon)
Tazobactam, usually combined with piperacillin (Zosyn) (Tazocin)
Avibactam, approved in combination with ceftazidime (Avycaz), currently undergoing clinical trials for combination with ceftaroline

Beta-lactamase producing bacteria

Bacteria that can produce beta-lactamases include, but are not limited to:

MRSA
Staphylococcus
Enterobacteriaceae
Haemophilus influenzae
Neisseria gonorrhoeae
Klebsiella pneumoniae
Citrobacter
Morganella

Research

Some bacteria can produce extended spectrum β-lactamases (ESBLs) making the infection more difficult to treat and conferring additional resistance to penicillins, cephalosporins, and carbapenems.^[11] Boronic acid derivatives are currently under vast and extensive research as novel active site inhibitors for beta-lactamases because they contain a site that mimics the transition state that beta-lactams go through when undergoing hydrolysis via beta-lactamases. They have been found generally to fit well into the active site of many beta-lactamases and have the convinient property of being unable to be hydrolysed, and therefore rendered useless. This is a favorable drug design over many clinically used competing agents, because most of them, such as clavulonic acid, become hydrolysed, and are therefore only useful for a finite period of time. This generally causes the need for a higher concentration of competitive inhibitor than would be necessary in an unhydrolyzable inhibitor. Different boronic acid derivatives have to potential to be tailored to the many different isoforms of beta-lactamses, and therefore have the potential to reestablish potency of beta-lactam antibiotics.^[12]

References

^ Essack SY (2001). "The development of beta-lactam antibiotics in response to the evolution of beta-lactamases". Pharm. Res. 18 (10): 1391–9. PMID 11697463.
^ "Beta-Lactamase Inhibitors". Department of Nursing of the Fort Hays State University College of Health and Life Sciences. October 2000. Archived from the original on 2007-09-27. Retrieved 2007-08-17.
^ Georgopapadakou NH (1993). "Penicillin-binding proteins and bacterial resistance to beta-lactams". Antimicrob. Agents Chemother. 37 (10): 2045–53. PMC 192226. PMID 8257121.
^ Zapun A, Contreras-Martel C, Vernet T (2008). "Penicillin-binding proteins and beta-lactam resistance". FEMS Microbiol. Rev. 32 (2): 361–85. doi:10.1111/j.1574-6976.2007.00095.x. PMID 18248419.
^ Curello J, MacDougall C (2014). "Beyond Susceptible and Resistant, Part II: Treatment of Infections Due to Gram-Negative Organisms Producing Extended-Spectrum β-Lactamases". J Pediatr Pharmacol Ther 19 (3): 156–64. doi:10.5863/1551-6776-19.3.156. PMC 4187532. PMID 25309145.
^ Wolter DJ, Lister PD (2013). "Mechanisms of β-lactam resistance among Pseudomonas aeruginosa". Curr. Pharm. Des. 19 (2): 209–22. PMID 22894618.
^ Drawz SM, Bonomo RA (2010). "Three decades of beta-lactamase inhibitors". Clin. Microbiol. Rev. 23 (1): 160–201. doi:10.1128/CMR.00037-09. PMC 2806661. PMID 20065329.
^ Biedenbach D, Bouchillon S, Hackel M, Hoban D, Kazmierczak K, Hawser S, Badal R (2015). "Dissemination of NDM metallo-β-lactamase genes among clinical isolates of Enterobacteriaceae collected during the SMART global surveillance study from 2008 to 2012". Antimicrob. Agents Chemother. 59 (2): 826–30. doi:10.1128/AAC.03938-14. PMC 4335866. PMID 25403666.
^ Drawz SM, Bonomo RA (2010). "Three decades of beta-lactamase inhibitors". Clin. Microbiol. Rev. 23 (1): 160–201. doi:10.1128/CMR.00037-09. PMC 2806661. PMID 20065329.
^ Watson ID, Stewart MJ, Platt DJ (1988). "Clinical pharmacokinetics of enzyme inhibitors in antimicrobial chemotherapy". Clin Pharmacokinet 15 (3): 133–64. doi:10.2165/00003088-198815030-00001. PMID 3052984.
^ Livermore, David M. (October 1995). "β-Lactamases in Laboratory and Clinical Resistance". Clinical Microbiology Reviews 8 (4): 557–84. PMC 172876. PMID 8665470.
^ Leonard, David A.; Bonomo, Robert A.; Powers, Rachel (2012). "Class D β‑Lactamases: A Reappraisal after Five Decades". Accounts of Chemical Reseach.

External links

Xu, Hua; Hazra, Saugata; Blanchard, John S. (2012). "NXL104 Irreversibly Inhibits the β-Lactamase from Mycobacterium tuberculosis". Biochemistry 51 (22): 4551–7. doi:10.1021/bi300508r. PMID 22587688.
Kurz, Sebastian G.; Wolff, Kerstin A.; Hazra, Saugata; Bethel, Christopher R.; Hujer, Andrea M.; Smith, Kerri M.; Xu, Yan; Tremblay, Lee W.; Blanchard, John S.; Nguyen, Liem; Bonomo, Robert A. (2013). "Can Inhibitor-Resistant Substitutions in the Mycobacterium tuberculosis β-Lactamase BlaC Lead to Clavulanate Resistance?: a Biochemical Rationale for the Use of β-Lactam–β-Lactamase Inhibitor Combinations". Antimicrobial Agents and Chemotherapy 57 (12): 6085–96. doi:10.1128/AAC.01253-13. PMID 24060876.

UpToDate Contents

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1. β-ラクタマーゼ阻害剤、カルバペネム系、およびモノバクタム系抗菌薬の併用 combination beta lactamase inhibitors carbapenems and monobactams
2. β-ラクタム系抗生物質：作用機序、耐性および有害作用 beta lactam antibiotics mechanisms of action and resistance and adverse effects
3. 基質特異性拡張型β-ラクタマーゼ extended spectrum beta lactamases
4. ペニシリン penicillins
5. 壊死性軟部組織感染症 necrotizing soft tissue infections

English Journal

Ceftolozane-tazobactam: A new-generation cephalosporin.

Cluck D1, Lewis P2, Stayer B2, Spivey J2, Moorman J2.
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.Am J Health Syst Pharm.2015 Dec 15;72(24):2135-46. doi: 10.2146/ajhp150049.
PURPOSE: The chemistry, pharmacokinetic and pharmacodynamic properties, efficacy, and safety of the recently introduced combination antimicrobial agent ceftolozane-tazobactam are reviewed.SUMMARY: Ceftolozane-tazobactam (Zerbaxa, Cubist Pharmaceuticals) is a cephalosporin β-lactam and β-lactamase
PMID 26637512

Frequency of Plasmid-Mediated AmpC β-Lactamases in Escherichia coli Isolates from Urine Samples in São Paulo, Brazil.

Rocha DA1, Campos JC1, Passadore LF2, Sampaio SC3, Nicodemo AC4, Sampaio JL1,5.
Microbial drug resistance (Larchmont, N.Y.).Microb Drug Resist.2015 Dec 15. [Epub ahead of print]
Plasmid-mediated AmpC β-lactamases (PMACBLs) in Enterobacteriaceae encode resistance to third-generation cephalosporins, and these can mediate carbapenem resistance when associated with porin loss. However, no standardized phenotypic method is available for detecting these enzymes in the clinical m
PMID 26670152

Comparison of Verona Integron-Borne Metallo-β-lactamase Variants Reveals Differences in Stability and Inhibition Profiles.

Makena A1, Düzgün AÖ2, Brem J1, McDonough MA1, Rydzik AM1, Abboud MI1, Saral A3, Çiçek AÇ4, Sandalli C5, Schofield CJ6.
Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2015 Dec 14. pii: AAC.01768-15. [Epub ahead of print]
Metallo-β-lactamases (MBLs) are of increasing clinical significance; the development of clinically useful MBL inhibitors is challenged by the rapid evolution of variant MBLs. The Verona Integron-borne metallo-β-lactamases (VIM) enzymes are among the most widely distributed MBLs; with >40 VIM va
PMID 26666919

Japanese Journal

β-ラクタマーゼ阻害剤配合抗生物質注射剤のサル単回前房内投与による眼毒性試験

あたらしい眼科 = Journal of the eye 25(1), 89-93, 2008-01-30
NAID 10022616890

誤嚥性肺炎の起炎菌として高頻度に分離される口腔内細菌の薬剤感受性

日本化学療法学会雑誌 55(5), 378-381, 2007
NAID 130004298331

A Theoretical Study on the Substrate Deacylation Mechanism of Class C beta-Lactamase

Journal of Physical Chemistry B 109(33), 16153-16160, 2005-08-25
NAID 80017590006

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リンク元	「βラクタマーゼ阻害薬」「ラクタマーゼ阻害薬」「βラクタマーゼ阻害剤」
関連記事	「inhibit」「inhibitor」「lactamase」「beta」「be」