Semisynthetic .BETA.-lactam antibiotics. IV. Synthesis and antibacterial activity of new ureidocephalosporin and ureidocephamycin derivatives containing a catechol moiety or its acetate.

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

doi:10.1248/cpb.35.1903

Cited by 23 publications

(11 citation statements)

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“…Related catechol derivatives of ureidocephalosporins and ureidocephamycins also displayed enhanced activity against P. aeruginosa (45). It was speculated that all of these compounds owed their enhanced antimicrobial activity to their ability to bind iron and be actively carried into cells by iron transport mechanisms.…”

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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“…In recent years, new ␤-lactam antibiotics that possess a catechol or pyridone moiety have been synthesized and reported to show potent antibacterial activities against most gram-negative bacteria, including P. aeruginosa, which have low levels of outer membrane permeability (29,32,35,38,39,41,42). This enhanced activity was due to the ability to bind iron and to undergo active transport into cells by iron transport mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of tonB-dependent transport of KP-736, a 1,5-dihydroxy-4-pyridone-substituted cephalosporin, into Escherichia coli K-12 cells

Tatsumi¹,

Maejima²,

Mitsuhashi³

1995

Antimicrob Agents Chemother

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The mechanism of transport of KP-736, a novel cephalosporin with a 1,5-dihydroxy-4-pyridone moiety at the C-7 position, into the Escherichia coli K-12 cell was investigated by determining the susceptibilities of iron transport mutants to KP-736. The tonB mutant showed a higher degree of resistance to KP-736, indicating that KP-736 was incorporated into E. coli cells via the tonB-dependent iron transport system. The product of the exbB gene was also necessary for the maximal antibacterial potency of KP-736. Cir-lacking and Fiu-lacking mutants showed a moderate level of resistance to KP-736. However, mutants lacking any one of the proteins FepA, FecA, FhuA, and FhuE did not show any increased resistance to KP-736. Two types of spontaneous mutants (e.g., KT1004 and KT1011) could be isolated from cir and fiu mutants by selection for KP-736 resistance and showed the same level of resistance to KP-736 as a tonB mutant. KT1004 showed tonB phenotypes, resistance to phage 80, and loss of FecA, whereas KT1011 did not. KT1011 lost the ability to express both Cir and Fiu proteins. These results indicate that the Cir and Fiu outer membrane proteins are involved specifically in the tonB-dependent transport process of KP-736. Against OmpF-and OmpC-deficient transformants producing various groups of ␤-lactamases, KP-736 was more effective than the other cephalosporins tested.

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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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Semisynthetic .BETA.-lactam antibiotics. IV. Synthesis and antibacterial activity of new ureidocephalosporin and ureidocephamycin derivatives containing a catechol moiety or its acetate.

Cited by 23 publications

References 0 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

Mechanism of tonB-dependent transport of KP-736, a 1,5-dihydroxy-4-pyridone-substituted cephalosporin, into Escherichia coli K-12 cells

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

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