Semisynthetic .BETA.-lactam antibiotics. I. Synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties.

Ohi, Nobuhiro; Aoki, Bunya; Shinozaki, Teizo; Moro, Kanzi; Noto, Takao; Nehashi, Toshiyuki; Okazaki, Hiroshi; Matsunaga, Isao

doi:10.7164/antibiotics.39.230

Cited by 42 publications

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“…These data suggested that the full expression of iron-regulated outer membrane proteins is important for in vivo growth. DISCUSSION Recently, ureidopenicillins having a terminal catechol moiety were synthesized and found to have 30-to 60-fold increase in activity relative to piperacillin against various microbes, including Pseudomonas aermginosa strains, which are generally less susceptible to 1-lactam antibiotics (44,46).…”

Section: Resultsmentioning

confidence: 99%

Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria

Brochu

Nicas

et al. 1992

Antimicrob Agents Chemother

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We describe here the mechanism of inhibition of two new siderophore-13-lactam conjugates against Escherichia coil X580. One conjugate is a spermidine-based catechol siderophore-carbacephalosporin (JAM-2-263), and the other is an N5-acetyl-Ns-hydroxy-L-ornithine tripeptide hydroxamate siderophore-carbacephalosporin . In an agar diffusion test, both conjugates produced large inhibitory zones against strain X580. Resistant strains (i.e., JAMR and EKD") could be isolated after exposure of X580 to the conjugates JAM-2-263 and EKID-3-88, respectively. No cross-resistance was observed in these individual isolates. JAMR and EKDR were studied further to elucidate the mechanism of inhibition of each conjugated drug. The affinities of JAM-2-263 and EKD-3-88 for penicillin-binding proteins (PBPs) of isolated inner membranes were determined by a competition assay with mI-penicillin V. JAM-2-263 targeted primarily PBPs IA/B and 5/6, while EKD-3-88 targeted PBPs lA/B and 3. Strains X580, JAMR, and EKDR showed similar PBP afinities for the conjugates. However, marked changes were observed in the iron-regulated outer membrane proteins of resistant isolates grown on agar plates depleted of iron. EKDR lost the expression of FhuA (78 kDa) and its sensitivity to phages Ti and T5, whereas JAMR lost the expression of Cir (74 kDa) and its sensitivity to colicin Ia. These results revealed the requirement of FhuA and Cir for the inhibitory activities of EKD-3-88 and JAM-2-263, respectively. In an antibiotic diffusion assay, ferrichrome (1 FLM) strongly antagonized the activities of both conjugates against X580 and JAMR, including the residual activity of JAM-2-263 against JAMR. However, the susceptibility of strain EKDR lacking the ferrichrome receptor (FhuA-) to the two conjugates remained the same in the presence of ferrichrome. The antagonistic effect of ferrichrome on the activity of JAM-2-263 may also indicate a role for FhuA in the activity of this 13-lactam conjugate. A FhuACir-double mutant confirmed this hypothesis, since it showed a higher level of resistance to JAM-2-263. To reproduce iron-restricted in vivo growth conditions, we grew X580 and EKDR cells in diffuision chambers implanted in the peritoneal cavities of rats. Strain EKDR showed impaired growth in such a cultivation system.

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Section: Resultsmentioning

confidence: 99%

Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria

Brochu

Nicas

et al. 1992

Antimicrob Agents Chemother

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“…Thus, Escherichia coli, for example, is known to have at least seven outer membrane proteins whose production is regulated by the availability of ferric iron in the environment; four of them, the products of the fepA, fecA, fluA, and AhuE genes, have been identified as the receptors for ferric enterobactin, ferric citrate, fermchrome, and coprogen, respectively (12,22). Recently, several P-lactam compounds with attached iron-chelating moieties have been developed (9,18,24). Moreover, evidence suggestive of the utilization of a siderophore receptor for outer membrane penetration was obtained for at least one of these compounds, E0702, because E. coli became resistant to this compound if it had tonB mutations, which abolish the transport of all known siderophores as well as vitamin B12 across the outer membrane (26).…”

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confidence: 99%

Cir and Fiu proteins in the outer membrane of Escherichia coli catalyze transport of monomeric catechols: study with beta-lactam antibiotics containing catechol and analogous groups

1990

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Recently, j8-lactam agents containing iron-chelating moieties, such as E0702, which contains catechol, and pirazmonam and U-78,608, which contain 3-hydroxypyridone, have been developed. By determining the susceptibility to these agents of Escherichia coli mutants lacking various iron-repressible outer membrane proteins, we showed that two of these proteins with hitherto unknown functions, Fiu and Cir, were apparently involved in the transport of monomeric catechol and its analogs. These results confirm the conclusion of Curtis and co-workers, which was obtained by using a different set of catechol-containing antibiotics (N. A. C. Curtis, R. L. Eisenstadt, S. J. East, R. J. Cornford, L. A. Walker, and A. J. White, Antimicrob. Agents Chemother. 32:1879Chemother. 32: -1886Chemother. 32: , 1988. E0702 was shown to enhance the uptake of radioactive ferric iron into wild-type cells but not into cir fiu double mutants. By combining the influx of E0702 with its hydrolysis by a periplasmic P-lactamase, we showed that the wild-type cells transported unliganded E0702 at a rate comparable to or even higher than the rate of transport of the E0702-Fe3+ complex. We postulate that the main function of Cir and Fiu may be to recapture the hydrolytic products of enterobactin, such as 2,3-dihydroxybenzoic acid and 2,3-dihydroxybenzoylserine.Most nutrients used by gram-negative bacteria move across the outer membrane through the nonspecific channels of porin (16), and a similar mechanism of diffusion is thought to be used by most antibiotics that are effective against these bacteria, including most ,-lactams (13). Some nutrients, however, are too large for efficient diffusion through the porin channel, and these compounds, including iron-siderophore complexes, are often taken up by specific pathways present in the outer membrane. Thus, Escherichia coli, for example, is known to have at least seven outer membrane proteins whose production is regulated by the availability of ferric iron in the environment; four of them, the products of the fepA, fecA, fluA, and AhuE genes, have been identified as the receptors for ferric enterobactin, ferric citrate, fermchrome, and coprogen, respectively (12,22). Recently, several P-lactam compounds with attached iron-chelating moieties have been developed (9,18,24). Moreover, evidence suggestive of the utilization of a siderophore receptor for outer membrane penetration was obtained for at least one of these compounds, E0702, because E. coli became resistant to this compound if it had tonB mutations, which abolish the transport of all known siderophores as well as vitamin B12 across the outer membrane (26). However, the identities of the outer membrane receptors used by these 1-lactams were unknown, and this study was undertaken to identify these receptors. In the course of the present study, we learned that another laboratory studied the outer membrane permeation of a group of catechol-containing cephalosporins by using a similar approach (3). Our results, however, have been obtained by using an...

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“…[12][13][14][15][16][17] Through the tonB dependent iron transport mechanism, 18) the use of catechol substituted b-lactams was known to increase the drug's penetration into the bacterial cell walls. Thus, several catechol-substituted blactams have been synthesized and showed good antimicrobial activities.…”

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Novel .BETA.-Lactam Antibiotics Synthesized by Amination of Catechols Using Fungal Laccase

et al. 2008

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In preceding papers, we discussed the laccase-catalyzed amination of 2,5-dihydroxybenzoic acid derivatives with aminopenicillins and aminocephalosporins.2,3) The motive for our work was the global issue with resistant pathogenic bacteria, e.g. Streptococcus pneumoniae strains [4][5][6][7] and Staphylococcus strains, against currently available b-lactam antibiotics. [8][9][10][11] Aminated products like 2-(3,6-dioxocyclohexa-1,4-dienylamino)-2-phenyl-acetylamino-penicillanic acids and 2-(3,6-dioxocyclohexa-1,4-dienylamino)-2-phenyl-acetylamino-cephalosporanic acids 2,3) inhibited the growth of several Gram positive bacterial strains and protected mice against an infection with Staphylococcus aureus. After amination the 2,5-dihydroxybenzoic acid derivatives were units of the C-7 substituent of the b-lactam antibiotics.The possibility of utilizing catechol units as an element of the C-7 substituent of penicillins and cephalosporins was investigated for a long time. [12][13][14][15][16][17] Through the tonB dependent iron transport mechanism, 18) the use of catechol substituted b-lactams was known to increase the drug's penetration into the bacterial cell walls. Thus, several catechol-substituted blactams have been synthesized and showed good antimicrobial activities. [19][20][21][22][23] As a consequence of the promising activity of the catechol substituted b-lactams on one hand and the novel laccase-synthesized b-lactams on the other hand, we got interested in laccase-catalyzed amination of catechols with aminopenicillins and aminocephalosporins.In this study, we have employed laccase from Trametes sp. to derivatize amino-b-lactams and to couple them both with catechol and with substituted catechols. The novel b-lactams were structurally characterized as new coupling products inhibiting the growth of several Gram positive bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. The cytotoxicity of the new compounds and the effectiveness in a "Staphylococcus-infected, immune suppressed mouse" model are discussed. Results and DiscussionBiotransformation of Amino-b b-lactams by LaccasesLaccase-catalyzed reaction between catechols (substrates 1a to 1c) on one hand and the amino-b-lactams cefadroxil 2a, amoxicillin 2b, ampicillin 2c, and the structurally related carbacephem loracarbef 2d on the other hand led to cross coupled products (Table 1). 3-Methylcatechol and amino-b-lactams were consumed after an incubation time of 1.5 h, and monoaminated products (3a to 3d) were detectable by high-performance liquid chromatography (HPLC). If other catechols or longer reaction times were used, monoaminated products were only obtained in low yields and undesirable side reactions produced a number of by-products. Reaction kinetics similar to these findings were described for hybrid dimer formation from 3,4-dichloroaniline and syringic acid 24) or 3-(3,4-dihydroxy-phenyl)-propionic acid and 4-aminobenzoic acid. 25) In contrast, for hybrid dimer form...

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Semisynthetic .BETA.-lactam antibiotics. I. Synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties.

Abstract: The synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties in the 6-acyl side chain are described. These compounds showed remarkably strong VOL. XXXIX NO. 2 THE JOURNAL OF ANTIBIOTICS 231

Cited by 42 publications

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Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria

Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria

Cir and Fiu proteins in the outer membrane of Escherichia coli catalyze transport of monomeric catechols: study with beta-lactam antibiotics containing catechol and analogous groups

Novel .BETA.-Lactam Antibiotics Synthesized by Amination of Catechols Using Fungal Laccase

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