54600-89-4Relevant academic research and scientific papers
Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-β-lactamases
Chen, Fangfang,Hu, Liqiang,Ji, Changge,Liu, Runqiu,Mao, Wuyu,Wang, Hao,Xie, Hexin,Xue, Shuyuan,Yang, Huixin,Yu, Tao,Zhang, Shuangzhan
, (2022/02/14)
Antibiotic resistance caused by β-lactamases, particularly metallo-β-lactamases, has been a major threat to public health globally. New Delhi metallo-β-lactamase-1 (NDM-1) represents one of the most important metallo-β-lactamases; the production of NDM-1 in bacterial pathogen significantly reduces the efficacy of β-lactam antibiotics, including life-saving carbapenems. Herein, we have demonstrated stereochemically altered cephalosporins as potent inhibitors against NDM-1, as well as mutants of NDM. The structure and activity relationship (SAR) study on over twenty cephalosporin analogues discloses the stereochemistry and the substituents on 7-position and 3′-position of cephalosporin are critical to suppress the activity of NDM-1 and the optimal compound 1u exhibited an IC50 of 0.13 μM. Furthermore, a crystal complex of NDM-1 and 1u has been obtained, suggesting this cephalosporin derivative inhibits enzyme activity by the formation of a relatively stable hydrolytic product-NDM-1 intermediate. The discovery in this study may pave the way to turn cephalosporin, a natural substrate of β-lactamase, into an effective NDM-1 inhibitor to combat antibiotic resistance.
Specific detection ofIMP-1β-lactamase activity using atranscephalosporin-based fluorogenic probe
Chen, Fangfang,Hu, Liqiang,Li, Ziyao,Liu, Runqiu,Ma, Zheng,Xie, Hexin,Yu, Tao,Yuan, Chang,Zou, Yingqiu
supporting information, p. 13586 - 13589 (2021/12/23)
A fluorogenic probe for the specific detection ofIMP-1β-lactamase activity has been developed. This imaging reagent features a uniquetrans-acetylamino cephalosporin as an enzymatic recognition moiety, exhibiting excellent selectivity toIMP-1β-lactamase ov
Ratiometric fluorescence detection of pathogenic bacteria resistant to broad-spectrum β-lactam antibiotics
Zhang, Junxiang,Shen, Yang,May, Sarah L.,Nelson, Daniel C.,Li, Shuwei
supporting information; experimental part, p. 1865 - 1868 (2012/04/04)
Identification of bacteria: A methoxyimino cephalosporin derivative containing a pair of fluorescence resonance energy transfer (FRET) fluorophores was synthesized. This probe displays selective cleavage toward different types of β-lactamases, thereby pro
Toward the development of a cephalosporin-based dual-release prodrug for use in ADEPT
Grant, Jonathan W.,Smyth, Timothy P.
, p. 7965 - 7970 (2007/10/03)
In previous work we have shown that a cephalosporin structure bearing an S-aminosulfenimine at the 7-position behaved as a β-lactamase-dependent dual-release prodrug. Scission of the β-lactam ring of such a structure led to the rapid loss of the sulfur-at
The perfect penicillin? Inhibition of a bacterial DD-peptidase by peptidoglycan-mimetic β-lactams
Josephine, Helen R.,Kumar, Ish,Pratt
, p. 8122 - 8123 (2007/10/03)
6-(Glycyl-L-α-aminopimelyl)-aminopenicillanic acid and 7-(glycyl-L-α-aminopimelyl)-aminocephalosporanic acid have been synthesized as Streptomyces sp. peptidoglycan-mimetic β-lactams. These compounds inactivate the Streptomyces R61 DD-peptidase with rate
Antimicrobial effects of novel siderophores linked to β-lactam antibiotics
Kline,Fromhold,McKennon,Cai,Treiberg,Ihle,Sherman,Schwan,Hickey,Warrener,Witte,Brody,Goltry,Barker,Anderson,Tanaka,Shawar,Nguyen,Langhorne,Bigelow,Embuscado,Naeemi
, p. 73 - 93 (2007/10/03)
As a strategy to increase the penetration of antibiotic drugs through the outer membrane of Gram-negative pathogens, facilitated transport through siderophore receptors has been frequently exploited. Hydroxamic acids, catechols, or very close isosteres of catechols, which are mimics of naturally occurring siderophores, have been used successfully as covalently linked escorting moieties, but a much wider diversity of iron binding motifs exists. This observation, coupled to the relative lack of specificity of siderophore receptors, prompted us to initiate a program to identify novel, noncatechol siderophoric structures. We screened over 300 compounds for their ability to (1) support growth in low iron medium of a Pseudomonas aeruginosa siderophore biosynthesis deletion mutant, or (2) compete with a bactericidal siderophore-antibiotic conjugate for siderophore receptor access. From these assays we identified a set of small molecules that fulfilled one or both of these criteria. We then synthesized these compounds with functional groups suitable for attachment to both monobactam and cephalosporin core structures. Siderophore-β-lactam conjugates then were tested against a panel of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus strains. Although several of the resultant chimeric compounds had antimicrobial activity approaching that of ceftazidime, and most compounds demonstrated very potent activity against their cellular targets, only a single compound was obtained that had enhanced, siderophore-mediated antibacterial activity. Results with tonB mutants frequently showed increased rather than decreased susceptibilities, suggesting that multiple factors influenced the intracellular concentration of the drugs. (C) 2000 Elsevier Science Ltd.
Extending the β-lactamase-dependent prodrug armory: S- aminosulfeniminocephalosporins as dual-release prodrugs
Smyth, Timothy P.,O'Connor, Michael J.,O'Donnell, Michael E.
, p. 3132 - 3138 (2007/10/03)
Cephalosporins bearing an S-aminosulfenimine (R'(R'')NSN=) side chain at the 7-position are prototypic examples of a novel class of β-lactamase- dependent prodrug. Enzyme-catalyzed hydrolysis of the β-lactam ring in these structures triggers release of both the 3'-acetoxy group and the side chain sulfur-attached S-amino moiety as R'(R'')NH. This reactivity pattern should allow site-specific corelease of two distinct drug components from a cephalosporin, thereby providing a singular enhancement to the capacity of a cephalosporin as a prodrug nucleus; a key advantage of a dual-release prodrug is the potential to establish synergy between the coreleased structures. Areas for exploitation of this new structure type are antibody-directed enzyme prodrug therapy (ADEPT), which is a key emerging anticancer therapy, and the further development of site-specific-release prodrugs to combat the problem of β-lactamase-based resistance to antibiotics.
7-ALKYLIDENE CEPHALOSPORANIC ACID DERIVATIVES AND METHODS OF USING THE SAME
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, (2008/06/13)
Derivatives of 7-alkylidene cephalosporanic acid sulfone and the pharmaceutically active salts thereof are found to be potent inhibitors of beta-lactamase enzymes.
7-VINYLIDENE CEPHALOSPORINS AND METHODS OF USING THE SAME
-
, (2008/06/13)
Cephalosporins with an exocyclic allene in the 7-position and their pharmaceutically active salts are potent inhibitors of beta-lactamases and are therefore useful in the treatment of penicillin resistant infections
