Où achat cialis sans ordonnance et acheter viagra en France.

Pages.csam.montclair.edu

Overview
Metallo-
β-lactamase inhibitors: Promise for the future?
Jeffrey H Toney* & Joseph G Moloughney
number of metallo-•-lactamases (MBLs), three subclasses (B1, B2 and B3) have been characterized based on their known Department of Chemistry and Biochemistry sequences [4•]. MBLs expressed in Bacillus cereus (BcII), Richardson Hall Room 352 1 Normal Avenue Bacteroides fragilis (CcrA, also CfiA) and Pseudomonas aeruginosa (IMP-1) have been characterized in greatest detail. The IMP-1 enzyme is of particular interest since it is encoded by both plasmids and integrons [5]. These mobile fragments of DNA could be responsible for the future widespread dissemination of *To whom correspondence should be addressed Current Opinion in Investigational Drugs 2004 5(8):
X-ray crystal structures are now available for several MBLs, The Thomson Corporation ISSN 1472-4472 with and without bound inhibitors, and offer the potential for structure-aided drug design. Examples include BcII [6], IMP-1 Carbapenem resistance continues to erode the effectiveness of [7•,8•], CfiA [9•] and subclass B3 Stenotrophomonas maltophilia antibiotics such as imipenem and meropenem in the clinic. Resistance mechanisms can include interplay between porin loss (membrane (L-1) [10]. The crystal structure of IMP-1 bound to a permeability), mutation of penicillin binding proteins necessary for mercaptocarboxylate revealed three key interactions in the cell division, and expression of class A, B and D β-lactamases. enzyme active site and includes contacts between the inhibitor and a conserved lysine, the zinc atoms and a hydrophobic Bacterial resistance to β-lactams such as penicillin or amoxicillin has pocket. The X-ray crystal structure of subclass B1 been overcome in the clinic using several strategies, including Chryseobacterium meningosepticum (BlaB) MBL bound to an development of antibiotics not susceptible to hydrolysis by β- lactamases, or co-administration of the antibiotic with β-lactamase inhibitors. This overview will focus on progress since 2000 in MBL inhibitors reported prior to the year 2000 include identifying inhibitors of class B, or metallo-β-lactamases with the aim trifluoromethyl alcohols and ketones [12], thioester derivatives of reversing carbapenem resistance. [13-16], thiols [17], biphenyl tetrazoles [18,19], hydroxamates Keywords Antibiotics, antibiotic resistance, β-lactam antibiotics,
(amino-acid derived) [20], phenazines [21] and 1β- metallo-β-lactamases, metallo-β-lactamase inhibitors methylcarbapenems [22•,23•]. This overview presents novel chemical classes of MBL inhibitors reported since 2000. Introduction
β-Lactam antibiotics have proven to be an overwhelming N-arylsulfonyl hydrazones
success in the treatment of bacterial infections. The dynamic
N-arylsulfonyl hydrazones are inhibitors of IMP-1. This nature of bacteria allows for their alarmingly facile adaptation chemical class is exemplified by compound 1 (Figure 1) [24], the to a changing environment. Bacteria have developed several most potent inhibitor of the series. Compound 1 exhibited a K i mechanisms of resistance to antibiotics. The reduced value of 0.7 ± 0.1 µM, characteristic of a competitive inhibitor. permeability of the cell wall [1], alterations in target enzymes Exploration of this chemical class revealed that enzyme (penicillin-binding proteins) [2] and production of various inhibition increased with bulky aromatic substituents that had forms of β-lactamase all contribute to the diminishing little electron withdrawing capacity (eg, compound 1 versus effectiveness of antibiotics. β-Lactamases have been grouped compound 3 (Figure 1)). Activity against the BcII enzyme of this into four molecular classes [3•]; classes A, C and D are serine series was much weaker than that reported for IMP-1. No active site β-lactamases, while class B enzymes are antimicrobial synergy data involving the compounds was metalloproteins that are zinc dependent. Due to the growing Figure 1. N-arylsulfonyl IMP-1 inhibitors.
Succinic acids
against the L-1 enzyme was shown. SB-236049 (Table 1) was Screening of the Merck chemical collection led to the the most potent of the series, with IC values of ≤ 2 µM identification of a series of succinic acids that are potent against the CfiA and BcII enzymes. SB-238569 (Table 1) was inhibitors of IMP-1 [8•]. A 2,3-(S,S)-disubstituted succinic most effective against the CfiA enzyme with a K value of 3.4 acid was found to have an IC value of 0.0027 µM. X-ray µM. The tricyclic compounds showed no metal ion-chelating crystallography and molecular modeling, structure-activity activity when incubated in the presence of 100 µM ZnSO . In relationships studies revealed that potent inhibition addition, the compounds displayed selectivity against MBLs required two hydrophobic groups on the succinic acid by exhibiting minimal or no inhibition against the center in a (2S,3S) configuration. Representative succinic mammalian metalloprotein ACE. The tricyclic inhibitors acids increased sensitivity to imipenem in carbapenem- displayed synergy with meropenem in bacterial strains resistant clinical isolates of P aeruginosa [25]. Thiomandelic acid
Mercaptocarboxylate
Thiols and mercaptoacetic acid thiol esters are reported to be A mercaptocarboxylate compound, 2-[5-(1-tetrazolylmethyl)- broad spectrum MBL inhibitors [26]. Recently, thiolate- thien-3-yl]-N-[2-(mercaptomethyl)-4(phenyl-butyrylglycine)] disulfide exchange has been used as a novel strategy to was found to be a potent inhibitor (IC = 90 nM) of IMP-1. In inhibit the MBL CcrA from B fragilis [27•]. D-captopril, an addition, B fragilis (CfiA) and S maltophilia (L1) enzymes angiotensin-converting enzyme (ACE) inhibitor used to treat were inhibited by the compound with IC values in the hypertension, has been shown to inhibit of the MBL range of 100 to 500 nM. No antimicrobial synergy data on
expressed in C meningosepticum [11] as well as the MBL the compound were available.
expressed in Fluoribacter gormanni, FEZ-1 [28]. The most
potent compounds contained both thiol and carboxylate Cysteinyl peptides
functional groups. The thiol group was necessary for Kinetic studies have shown that cysteinyl peptides are inhibition of the enzyme while the carboxylate group was competitive inhibitors of the B cereus (BcII) enzyme [29]. The not critical. Comparison of compounds 4, 7 and 8 (Figure 2) thiol group is believed to be necessary for inhibition as this reveals that inhibition of the B cereus BcII enzyme is greatest functional group coordinates to the zinc ion located in the when the thiol and carboxylate functional groups are in active site of the enzyme. The thiol inhibitors were non- proximity. Thiomandelic acid and two para-substituted chelators but enzyme inhibition by dithiol derivatives were analogs were the most effective inhibitors (compounds 4, 5 dependent on zinc ion concentration. N-carbobenzoxy-D- and 6; Figure 2) and thiomandelic acid was a competitive cysteinyl-D-phenylalanine was the most potent inhibitor of inhibitor of the BcII enzyme. In addition, thiomandelic acid the BcII enzyme with a K value of 3.0 µM. No antimicrobial was an effective inhibitor (K ≤ 0.80 µM) for eight distinct MBLs included in the study except for the Aeromonas hydrophilia (CphA) enzyme. No antimicrobial synergy data were provided. Thioxocephalosporin and penicillin-derived
inhibitors

Tricyclic natural products
Recently, the hydrolytic product of thioxocephalosporin, a Tricyclic compounds were identified and extracted from the thioacid, was found to be a modest inhibitor of B cereus fungal strain Chaetomium funicola. When tested for inhibition (BcII) [30], and demonstrated competitive inhibition with a against B cereus (BcII), P aeruginosa (IMP-1), B fragilis (CfiA) K value of 96 µM. In addition, a thioamide, cyclic and S maltophilia (L-1) MBLs, these compounds competitivly thioxopiperazinedione, produced by intramolecular inhibited the BcII, IMP-1 and CfiA enzymes. No inhibition aminolysis of thioxocephalexin was shown to competitively Figure 2. Comparison of thiomandelic inhibitors of B cereus (BcII).
Ki values assume competitive inhibition (SD < 20%) Table 1. IC50 values for tricyclic natural product inhibitors.
Compound
IC50 (µM)
B cereus II
SB-236049
SB-236050
SB-238569
inhibit the BcII metallo-enzyme with a K value of 29 µM. A RP: The structure of beta-lactamases. Philos Trans R Soc
Lond B Biol Sci. 1980, 289:321-31.
separate report identified a series of (mercaptomethyl)- penicillinates with micromolar to sub-micromolar IC Galleni M, Lamotte-Brasseur J, Rossolini GM, Spencer J, Dideberg O, values for the L1 MBL and low micromolar IC values for Frere JM, the metallo-b-lactamase working group: Standard
numbering scheme for class B b-lactamases. Antimicrob Agents
the BcII MBL [31]. In general, the (mercaptomethyl)- Chemother 2001, 45:660-663.
penicillinate sulfones were better inhibitors of L1 and the • A consortium of research groups studying metallo-b-lactamases proposed a (mercaptomethyl)penicillinate sulfides displayed good standard numbering scheme of these enzymes to facilitate comparative analysis of protein structure and catalytic mechanisms. activity against BcII. Several of the inhibitors exhibited synergy with piperacillin against an IMP-1 producing strain Arakawa Y, Murakami M, Suzuki K, Ito H, Wacharotayankun R, Ohsuka of E coli and a single compound had activity against clinical S, Kato N, Ohta M: A novel integron-like element carrying the
metallo-beta-lactamase gene blaIMP
. Antimicrob Agents Chemother
isolates of P aeruginosa producing either VIM-1 or SPM-1. 1995, 39:1612-1615.
Fabiane SM, Sohi MK, Wan T, Payne DJ, Bateson JH, Mitchell T, Conclusions
Sutton BJ: Crystal structure of the zinc-dependent beta-lactamase
Several novel chemical classes of MBL inhibitors have been from Bacillus cereus at 1.9 A resolution: binuclear active site with
reported recently and there is now a rich source of structural features of a mononuclear enzyme. Biochemistry 1998, 37:12404-
12411.
information on the chemical details of the enzyme-inhibitor interaction. While none of these classes constitute the 'ideal Concha NO, Janson CA, Rowling P, Pearson S, Cheever CA, Clarke
BP, Lewis C, Galleni M, Frere JM, Payne DJ, et al.: Crystal structure
MBL inhibitor', the challenge for the pharmaceutical of the IMP-1 metallo beta-lactamase from Pseudomonas
industry will be to continue to explore the chemical classes aeruginosa and its complex with a mercaptocarboxylate inhibitor:
presented here for sufficient broad spectrum activity against binding determinants of a potent, broad-spectrum inhibitor.
Biochemistry 2000, 39:4288-4298.
the most important clinical pathogens expressing MBLs [32]. • The SmithKline Beecham group determined the X-ray crystal structure of the Careful monitoring of clinical isolates for the presence of IMP-1 MBL with and without an inhibitor bound, revealing that the MBLs, within the context of other important resistance "hydrophobic flap" extending above the enzyme active site is displaced 2.9 A mechanisms, will provide the ultimate test of whether development of an MBL inhibitor will add value to the 8. Toney JH, Hammond GG, Fitzgerald PM, Sharma N, Balkovec JM, current antibiotic armamentarium. Rouen GP, Olson SH, Hammond ML, Greenlee ML, Gao YD: Succinic
acids as potent inhibitors of plasmid-borne IMP-1 metallo-beta-
lactamase
. J Biol Chem 2001, 276:31913-31918.
References
The Merck group identified succinic acids as potent IMP-1 inhibitors via high throughput screening. The X-ray crystal structure of the enzyme bound to two different succinic acids was determined. Interplay of impermeability and chromosomal beta-
lactamase activity in imipenem-resistant Pseudomonas 9.
Payne DJ, Hueso-Rodriguez JA, Boyd H, Concha NO, Janson CA, aeruginosa. Antimicrob Agents Chemother 1992, 36:2046-2048.
Gilpin M, Bateson JH, Cheever C, Niconovich NL, Pearson S, et al.: Identification of a series of tricyclic natural products as potent
Massova I, Mobashery S: Kinship and diversification of bacterial
broad-spectrum inhibitors of metallo-beta-lactamases. Antimicrob
penicillin-binding proteins and beta-lactamases. Antimicrob Agents
Agents Chemother 2002, 46:1880-1886.
Chemother 1998, 42:1-17.
The GlaxoSmithKline group identified tricyclic inhibitors using natural Extensive review on sequences alignments amongst penicillin-binding product screening and determined the X-ray structure of the CfiA MBL bound proteins and beta lactamases. 10. Ullah JH, Walsh TR, Taylor IA, Emery DC, Verma CS, Gamblin SJ, 22. Nagano R, Adachi Y, Imamura H, Yamada K, Hashizume T, Morishima Spencer J: The crystal structure of the L1 metallo-beta-lactamase
H: Carbapenem derivatives as potential inhibitors of various beta-
from Stenotrophomonas maltophilia at 1.7 A resolution. J Mol Biol
lactamases, including class B metallo-beta-lactamases. Antimicrob
1998, 284:125-136.
Agents Chemother 1999, 43:2497-2503.
The Banyu Tsukuba group showed that 1beta-methylcarbapenems can 11. Garcia-Saez I, Hopkins J, Papamicael C, Franceschini N, Amicosante sensitize resistant strains of IMP-1 producing Serratia marcescens when co- G, Rossolini GM, Galleni M, Frere JM, Dideberg O: The 1.5-A structure
of Chryseobacterium meningosepticum zinc beta-lactamase in
complex with the inhibitor, D-captopril. J Biol Chem 2003,
23. Nagano R, Adachi Y, Hashizume T, Morishima H: In vitro antibacterial
278:23868-23873.
activity and mechanism of action of J-111,225, a novel 1beta-
methylcarbapenem, against transferable IMP-1 metallo-beta-
12. Walter MW, Felici A, Galleni M, Paul-Soto R, Adlington RM, Baldwin JE, lactamase producers. J Antimicrob Chemother 2000, 45:271-276.
Frere JM, Gololobov M, Schofield CJ: Trifluoromethyl alcohol and
The Banyu Tsukuba group showed that 1beta-methylcarbapenems can ketone inhibitors of metallo-b-lactamases. Bioorg Med Chem Lett
sensitize resistant strains of IMP-1 producing Serratia marcescens as well as 1996, 6:2455-2458.
Pseudomonas aeruginosa in the presence of imipenem. 13. Greenlee ML, Laub JB, Balkovec JM, Hammond ML, Hammond GG, 24. Siemann S, Brewer D, Clarke AJ, Dmitrienko GI, Lajoie G, Viswanatha Pompliano DL, Epstein-Toney JH: Synthesis and SAR of thioester
IMP-1 metallo-beta-lactamase: effect of chelators and
and thiol inhibitors of IMP-1 metallo-beta-lactamase. Bioorg Med
assessment of metal requirement by electrospray mass
Chem Lett 1999, 9:2549-2554.
spectrometry. Biochim Biophys Acta 2002, 1571:190-200.
14. Hammond GG, Huber JL, Greenlee ML, Laub JB, Young K, Silver LL, 25. Huber J, Young K, Painter RE, Rosen H, Silver LL: Inhibition of IMP-1
Balkovec JM, Pryor KD, Wu JK, Leiting B, et al.: Inhibition of IMP-1
metallo-beta-lactamase in clinical isolates by two succinic acid
metallo-beta-lactamase and sensitization of IMP-1-producing
derivatives. 40th Interscience Conference on Antimicrobial Agents and
bacteria by thioester derivatives. FEMS Microbiol Lett 1999, 179:289-
26. Mollard C, Moali C, Papamicael C, Damblon C, Vessilier S, Amicosante 15. Payne DJ, Bateson JH, Gasson BC, Khushi T, Proctor D, Pearson SC, G, Schofield CJ, Galleni M, Frere JM, Roberts GC: Thiomandelic acid,
Reid R: Inhibition of metallo-beta-lactamases by a series of thiol
a broad spectrum inhibitor of zinc beta-lactamases: kinetic and
ester derivatives of mercaptophenylacetic acid. FEMS Microbiol Lett
spectroscopic studies. J Biol Chem 2001, 276:45015-45023.
1997, 157:171-175.
27. Boerzel H, Koeckert M, Bu W, Spingler B, Lippard SJ: Zinc-Bound
16. Payne DJ, Bateson JH, Gasson BC, Proctor D, Khushi T, Farmer TH, Thiolate-Disulfide Exchange: A Strategy for Inhibiting Metallo-beta-
Tolson DA, Bell D, Skett PW, Marshall AC, et al.: Inhibition of metallo-
lactamases. Inorg Chem 2003, 42:1604-1615.
beta-lactamases by a series of mercaptoacetic acid thiol ester
This study proposes a novel mechanism for inactivation of metallo-beta- derivatives. Antimicrob Agents Chemother 1997, 41:135-140.
lactamases, targeting the Zn-bound Cys for thiolate-disulfide exchange. 17. Goto M, Takahashi T, Yamashita F, Koreeda A, Mori H, Ohta M, 28. Garcia-Saez I, Mercuri PS, Papamicael C, Kahn R, Frere JM, Galleni M, Arakawa Y: Inhibition of the metallo-beta-lactamase produced from
Rossolini GM, Dideberg O: Three-dimensional structure of FEZ-1, a
Serratia marcescens by thiol compounds. Biol Pharm Bull 1997,
monomeric subclass B3 metallo-beta-lactamase from Fluoribacter
20:1136-1140.
gormanii, in native form and in complex with D-captopril. J Mol Biol
2003, 325:651-660.
18. Toney JH, Fitzgerald PM, Grover-Sharma N, Olson SH, May WJ, Sundelof JG, Vanderwall DE, Cleary KA, Grant SK, Wu JK, et al.: 29. Bounaga S, Galleni M, Laws AP, Page MI: Cysteinyl peptide
Antibiotic sensitization using biphenyl tetrazoles as potent
inhibitors of Bacillus cereus zinc beta-lactamase. Bioorg Med Chem
inhibitors of Bacteroides fragilis metallo-beta-lactamase. Chem Biol
2001, 9:503-510.
1998, 5:185-196.
Metallo-beta-lactamase inhibitors: could they give old
19. Toney JH, Cleary KA, Hammond GG, Yuan X, May WJ, Hutchins SM, antibacterials new life? Curr Opin Investig Drugs 2003, 4:115-116.
Ashton WT, Vanderwall DE: Structure-activity relationships of
biphenyl tetrazoles as metallo-beta-lactamase inhibitors. Bioorg
31. Tsang WY, Dhanda A, Schofield CJ, Frere JM, Galleni M, Page MI: The
Med Chem Lett 1999, 9:2741-2746.
inhibition of metallo-beta-lactamase by thioxo-cephalosporin
derivatives. Bioorg Med Chem Lett 2004, 14:1737-9.
20. Walter MW, Hernandez Valladares M, Adlington RM, Amicosante G, Baldwin JE, Frere JM, Galleni M, Rossolini GM, Schofield CJ: 32. Buynak JD, Chen H, Vogeti L, Gadhachanda VR, Buchanan CA, Palzkill Hydroxymate inhibitors of aeromonas hydrophilia AE036 metallo-b-
T, Shaw RW, Spencer J, Walsh TR: Penicillin-derived inhibitors that
lactamases. 1999.
simultaneously target both metallo- and serine-beta-lactamases.
Bioorg Med Chem Lett 2004, 14:1299-304.
21. Gilpin ML, Fulston M, Payne D, Cramp R, Hood I: Isolation and
structure determination of two novel phenazines from a
Streptomyces with inhibitory activity against metallo-enzymes,
including metallo-beta-lactamase
. J Antibiot (Tokyo) 1995, 48:1081-
1085.

Source: http://pages.csam.montclair.edu/~thomasd/josephm.pdf

Microsoft word - arrow sumatriptan inj_nov 2010_cmi.doc

Arrow – Sumatriptan Injection Sumatriptan Injection 6mg/0.5mL What is in this leaflet Please read this leaflet carefully before you start using ARROW - SUMATRIPTAN Injection. This leaflet answers some common questions about ARROW - SUMATRIPTAN Injection. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist. All medic

M2m 5 & 6 08.pdf

Prostate Cancer Education & Information Support Program since July 1993 Man to Man (M2M) is an educational, not for profit, prostate cancer support program of the American Cancer Society. It is a forum for discussing medical developments & experiences. Protocols discussed at M2M meetings are sometimesbased on anecdotal information. It is always

Copyright © 2010-2014 Pdf Medic Finder