Semisynthetic .BETA.-lactam antibiotics. II. Effect on antibacterial activity of ureido N-substituents in the 6-((R)-2-(3-(3,4-dihydroxybenzoyl)-1-ureido)-2-phenylacetamido)penicillanic acids.

Ohi, Nobuhiro; Aoki, Bunya; Moro, Kanzi; Kuroki, Toshihiko; Sugimura, Naoyuki; Noto, Takao; Nehashi, Toshiyuki; Matsumoto, Masahiko; Okazaki, Hiroshi; Matsunaga, Isao

doi:10.7164/antibiotics.39.242

Cited by 20 publications

(11 citation statements)

References 26 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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“…The possibility of utilizing different aromatics as elements of the C‐6/C‐7 substituent of penicillins and cephalosporins to improve activity and properties of antibiotics has long been the subject of investigation 11–15.…”

Section: Introductionmentioning

confidence: 99%

Comparative analyses of laccase‐catalyzed amination reactions for production of novel β‐lactam antibiotics

Mikolasch¹,

Manda²,

Schlüter³

et al. 2012

Biotech and App Biochem

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Seven novel β-lactam antibiotics with activities against Gram-positive bacterial strains, among them methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, were synthesized by amination of 2,5-dihydroxyphenylacetic acid in usable yields (30-60%). These products protected mice against an infection with S. aureus lethal to the control animals. The results show the usefulness of laccase for the synthesis of potential new antibiotics, in addition to the interdependence of the laccase substrates, the amino coupling partners, and the product formation, yield, and activity. The syntheses of β-lactam antibiotics with 2,5-dihydroxyaromatic acid substructures (para-substituted) are then compared with those of 3,4-dihydroxyaromatic acid substructures (ortho-substituted). Para-substituted laccase substrates were better reaction partners in these syntheses than ortho-substituted compounds.

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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.…”

mentioning

confidence: 99%

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. II. Effect on antibacterial activity of ureido N-substituents in the 6-((R)-2-(3-(3,4-dihydroxybenzoyl)-1-ureido)-2-phenylacetamido)penicillanic acids.

Cited by 20 publications

References 26 publications

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

Comparative analyses of laccase‐catalyzed amination reactions for production of novel β‐lactam antibiotics

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

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