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1.
J Med Chem ; 67(8): 6705-6725, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38596897

RESUMEN

Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate procedures for salt preparation, and potential hypersensitivity. To address these issues, a series of novel catechol-conjugated derivatives were designed, synthesized, and evaluated. Extensive structure-activity relationships and structure-metabolism relationships (SMR) were conducted, leading to the discovery of a promising compound 86b (Code no. YFJ-36) with a new thioether linker. 86b exhibited superior and broad-spectrum in vitro antibacterial activity, especially against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of 86b in fluid medium at pH 6-8 was enhanced. 86b also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of 86b supported its further research and development.


Asunto(s)
Antibacterianos , Catecoles , Diseño de Fármacos , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Catecoles/química , Catecoles/farmacología , Catecoles/síntesis química , Animales , Relación Estructura-Actividad , Ratones , Bacterias Gramnegativas/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Acinetobacter baumannii/efectos de los fármacos , beta-Lactamas/farmacología , beta-Lactamas/síntesis química , beta-Lactamas/química , Cefalosporinas/farmacología , Cefalosporinas/síntesis química , Cefalosporinas/química , Descubrimiento de Drogas
2.
Molecules ; 26(19)2021 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-34641579

RESUMEN

Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin ß-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28-65%).


Asunto(s)
Cefalosporinas/síntesis química , Compuestos de Espiro/síntesis química , Catecoles/química , Estructura Molecular , Penicilinas/química
3.
J Med Chem ; 64(13): 9141-9151, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34182755

RESUMEN

In an attempt to exploit the hydrolytic mechanism by which ß-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-ß-lactamases (MBLs) in a spatiotemporally controlled fashion. While enzymatic hydrolysis of the ß-lactam ring was observed, it was not accompanied by inhibitor release. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (8), demonstrated potent inhibition of IMP-type MBLs. In addition, conjugate 8 was also found to greatly reduce the minimum inhibitory concentration of meropenem against IMP-producing bacteria. The results of kinetic experiments indicate that these prodrugs inhibit IMP-type MBLs by acting as slowly turned-over substrates. Structure-activity relationship studies revealed that both phenyl and carboxyl moieties of 8 are crucial for its potency. Furthermore, modeling studies indicate that productive interactions of the thiomandelic acid moiety of 8 with Trp28 within the IMP active site may contribute to its potency and selectivity.


Asunto(s)
Antibacterianos/farmacología , Cefalosporinas/farmacología , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/química , Cefalosporinas/síntesis química , Cefalosporinas/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/química
4.
Bioorg Med Chem Lett ; 40: 127928, 2021 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-33705899

RESUMEN

Four new aminothiazole-oximepiperidone cephalosporins (10a-10d) were synthesized, with their in vitro antibacterial activities against hospital isolated Gram-negative bacteria assessed. The results showed that compounds 10a-10d effectively inhibit a variety of Gram-negative bacteria. Compound 10a was the most potent compound, with comparable activity as ceftazidime. The combination of compound 10a and Avibactam was very active against almost all bacteria tested, which including multidrug resistant K. pneumoniae and A. baumannii. Compared to Avycaz, this combination is more potent against ESBL producing K. pneumoniae. Thus, the combination of 10a and Avibactam is of interest for further studies.


Asunto(s)
Antibacterianos/farmacología , Cefalosporinas/farmacología , Oximas/farmacología , Piperidonas/farmacología , Tiazoles/farmacología , Antibacterianos/síntesis química , Compuestos de Azabiciclo/farmacología , Cefalosporinas/síntesis química , Combinación de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Oximas/síntesis química , Piperidonas/síntesis química , Tiazoles/síntesis química
5.
Mini Rev Med Chem ; 20(18): 1908-1916, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32811410

RESUMEN

The need for new therapeutics and drug delivery systems has become necessary owing to the public health concern associated with the emergence of multidrug-resistant microorganisms. Among the newly discovered therapeutic agents is cefiderocol, which was discovered by Shionogi Company, Japan as an injectable siderophore cephalosporin. Just like the other ß-lactam antibiotics, cefiderocol exhibits antibacterial activity via cell wall synthesis inhibition, especially in Gram negative bacteria (GNB); it binds to the penicillin-binding proteins, but its unique attribute is that it crosses the periplasmic space of bacteria owing to its siderophore-like attribute; it also resists the activity of ß-lactamases. Among all the synthesized compounds with the modified C-7 side chain, cefiderocol (3) presented the best and well-balanced activity against multi-drug resistant (MDR) Gram negative bacteria, including those that are resistant to carbapenem. In this article, an overview of the recent studies on cefiderocol was presented.


Asunto(s)
Antibacterianos/farmacología , Cefalosporinas/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Cefalosporinas/síntesis química , Cefalosporinas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Cefiderocol
6.
J Med Chem ; 62(9): 4411-4425, 2019 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-31009558

RESUMEN

Expression of ß-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to ß-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a ß-lactamase-cleavable motif. The prodrug is only bactericidal after activation by ß-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse ß-lactamases; bactericidal activity was not observed in strains without ß-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target ß-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce ß-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.


Asunto(s)
Antibacterianos/farmacología , Cefalosporinas/farmacología , Ciprofloxacina/análogos & derivados , Ciprofloxacina/farmacología , Profármacos/farmacología , beta-Lactamasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Cefalosporinas/síntesis química , Cefalosporinas/metabolismo , Ciprofloxacina/metabolismo , Farmacorresistencia Microbiana/fisiología , Escherichia coli/efectos de los fármacos , Hidrólisis , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Profármacos/síntesis química , Profármacos/metabolismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacología
7.
Eur J Med Chem ; 155: 847-868, 2018 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-29960205

RESUMEN

The structure-activity relationship (SAR) for a novel series of catechol conjugated siderophore cephalosporins is described with their in vitro activities against multi-drug resistant Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Enterobacteriaceae. Cefiderocol (3) was one of the best molecules which displayed well-balanced and potent activities against multi-drug resistant Gram-negative pathogens including carbapenem resistant bacteria among the prepared compounds with the modified C-7 side chain and the modified C-3 side chain. Cefiderocol (3) is a highly promising parenteral cephalosporin for the treatment of multi-drug resistant Gram-negative infection.


Asunto(s)
Antibacterianos/farmacología , Cefalosporinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Cefalosporinas/síntesis química , Cefalosporinas/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Cefiderocol
8.
Curr Pharm Biotechnol ; 19(1): 30-42, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29745327

RESUMEN

BACKGROUND: Cephalosporins are the most widely used semisynthetic antibiotics, which acted on bacterial cell wall (peptidoglycan) synthesis. The key intermediate for fabricating about twothirds of cephalosporins in clinical use is 7-aminocephalosporanic acid (7-ACA), which is derived from chemical or enzymatic deacylation of the natural antibiotic cephalosporin C (CPC). The chemical deacylation process has been replaced by the enzymatic deacylation process because the chemical process required harsh conditions and released toxic waste. METHODS: A two-step enzymatic process that utilized D-amino acid oxidase (DAAO) and 7-ß-(4carboxybutanamido)-cephalosporanic acid acylase (GLA) for two successive reactions has been applied for the conversion of CPC to 7-ACA in an industrial scale. RESULTS: To simplify the process and lower costs, the one-pot enzymatic processes were developed by the application of the mono-enzymatic process (application of cephalosporin C acylase or the variants of GLA), di-enzymatic process (simultaneous action of DAAO and GLA) or the tri-enzymatic process (simultaneous action of DAAO, GLA and catalase) for direct conversion of CPC to 7-ACA. CONCLUSION: Here, we mainly focused on the description of these one-pot enzymatic processes and emphasized on the preparation of the involved biocatalysts.


Asunto(s)
Antibacterianos/síntesis química , Cefalosporinas/síntesis química , Química Farmacéutica/métodos , Amidohidrolasas/síntesis química , D-Aminoácido Oxidasa/síntesis química , Penicilina Amidasa/síntesis química , Estructura Secundaria de Proteína
9.
ACS Chem Biol ; 13(7): 1890-1896, 2018 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-29595947

RESUMEN

Emergence of antibiotic bacterial resistance has caused serious clinical issues worldwide due to increasingly difficult treatment. Development of a specific approach for selective visualization of resistant bacteria will be highly significant for clinical investigations to promote timely diagnosis and treatment of bacterial infections. In this article, we present an effective method that not only is able to selectively recognize drug resistant AmpC ß-lactamases enzyme but, more importantly, is able to interact with bacterial cell wall components, resulting in a desired localization effect on the bacterial surface. A unique and specific enzyme-responsive cephalosporin probe (DFD-1) has been developed for the selective recognition of resistance bacteria AmpC ß-lactamase, by employing fluorescence resonance energy transfer with an "off-on" bioimaging. To achieve the desired localization, a lipid-azide conjugate (LA-12) was utilized to facilitate its penetration into the bacterial surface, followed by copper-free click chemistry. This enables the probe DFD-1 to be anchored onto the cell surface. In the presence of AmpC enzymes, the cephalosporin ß-lactam ring on DFD-1 will be hydrolyzed, leading to the quencher release, thus generating fluorescence for real-time resistant bacterial screening. More importantly, the bulky dibenzocyclooctyne group in DFD-1 allowed selective recognition toward the AmpC bacterial enzyme instead of its counterpart ( e.g., TEM-1 ß-lactamase). Both live cell imaging and cell cytometry assays showed the great selectivity of DFD-1 to drug resistant bacterial pathogens containing the AmpC enzyme with significant fluorescence enhancement (∼67-fold). This probe presented promising capability to selectively localize and screen for AmpC resistance bacteria, providing great promise for clinical microbiological applications.


Asunto(s)
Bacterias/metabolismo , Proteínas Bacterianas/análisis , Cefalosporinas/química , Colorantes Fluorescentes/química , beta-Lactamasas/análisis , Proteínas Bacterianas/metabolismo , Cefalosporinas/síntesis química , Cefalosporinas/metabolismo , Farmacorresistencia Bacteriana , Enterobacter cloacae/enzimología , Enterococcus faecium/enzimología , Fluorescencia , Transferencia Resonante de Energía de Fluorescencia , Colorantes Fluorescentes/síntesis química , Hidrólisis , Staphylococcus aureus Resistente a Meticilina/enzimología , Pruebas de Sensibilidad Microbiana , Microscopía Confocal , Pseudomonas aeruginosa/enzimología , Pseudomonas putida/enzimología , Staphylococcus aureus/enzimología , beta-Lactamasas/metabolismo
10.
Artículo en Inglés | MEDLINE | ID: mdl-28971874

RESUMEN

Bacterial ß-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature ß-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D ß-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by "grafting" carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-α hydroxyethyl moiety to replace the original 6-ß aminoacyl group. MPC-1 selectively inhibits class C ß-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is ∼2 to 5 times higher than that for clinically used ß-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A ß-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel ß-lactamase inhibitors.


Asunto(s)
Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Penicilinas/síntesis química , Penicilinas/farmacología , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Sitios de Unión , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Carbapenémicos/química , Dominio Catalítico , Cefalosporinas/síntesis química , Cefalosporinas/química , Cefalosporinas/farmacología , Ácido Clavulánico/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Penicilinas/química , Estereoisomerismo , Sulbenicilina/farmacología , Inhibidores de beta-Lactamasas/química
11.
PLoS One ; 12(7): e0181563, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28749999

RESUMEN

We present the synthesis and biological evaluation of the prototype of a new class of cephalosporins, containing an additional isolated beta lactam ring with two phenyl substituents. This new compound is effective against Gram positive microorganisms, with a potency similar to that of ceftriaxone, a cephalosporin widely used in clinics and taken as a reference, and with no cytotoxicity against two different human cell lines, even at a concentration much higher than the minimal inhibitory concentration tested. Additionally, a deep computational analysis has been conducted with the aim of understanding the contribution of its moieties to the binding energy towards several penicillin-binding proteins from both Gram positive and Gram negative bacteria. All these results will help us developing derivatives of this compound with improved chemical and biological properties, such as a broader spectrum of action and/or an increased affinity towards their molecular targets.


Asunto(s)
Cefalosporinas/química , Cefalosporinas/síntesis química , Modelos Moleculares , Antibacterianos/farmacología , Ceftriaxona/síntesis química , Ceftriaxona/química , Ceftriaxona/farmacología , Supervivencia Celular/efectos de los fármacos , Cefalosporinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Proteínas de Unión a las Penicilinas/farmacología , Relación Estructura-Actividad , beta-Lactamas/farmacología
12.
Chem Commun (Camb) ; 52(40): 6727-30, 2016 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-27121860

RESUMEN

Bacterial metallo-ß-lactamases (MBLs) are involved in resistance to ß-lactam antibiotics including cephalosporins. Human SNM1A and SNM1B are MBL superfamily exonucleases that play a key role in the repair of DNA interstrand cross-links, which are induced by antitumour chemotherapeutics, and are therefore targets for cancer chemosensitization. We report that cephalosporins are competitive inhibitors of SNM1A and SNM1B exonuclease activity; both the intact ß-lactam and their hydrolysed products are active. This discovery provides a lead for the development of potent and selective SNM1A and SNM1B inhibitors.


Asunto(s)
Cefalosporinas/farmacología , Enzimas Reparadoras del ADN/antagonistas & inhibidores , Reparación del ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Exodesoxirribonucleasas/antagonistas & inhibidores , Proteínas Nucleares/antagonistas & inhibidores , beta-Lactamasas/metabolismo , Proteínas de Ciclo Celular , Cefalosporinas/síntesis química , Cefalosporinas/química , Enzimas Reparadoras del ADN/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Exodesoxirribonucleasas/metabolismo , Humanos , Modelos Moleculares , Conformación Molecular , Proteínas Nucleares/metabolismo , Relación Estructura-Actividad
13.
PLoS One ; 11(1): e0146488, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26820134

RESUMEN

The aim of this study was to investigate the relationship between antimicrobial use and the occurrence of antimicrobial resistance in the digestive and respiratory tract in three different production systems of food producing animals. A longitudinal study was set up in 25 Belgian bovine herds (10 dairy, 10 beef, and 5 veal herds) for a 2 year monitoring of antimicrobial susceptibilities in E. coli and Pasteurellaceae retrieved from the rectum and the nasal cavity, respectively. During the first year of observation, the antimicrobial use was prospectively recorded on 15 of these farms (5 of each production type) and transformed into the treatment incidences according to the (animal) defined daily dose (TIADD) and (actually) used daily dose (TIUDD). Antimicrobial resistance rates of 4,174 E. coli (all herds) and 474 Pasteurellaceae (beef and veal herds only) isolates for 12 antimicrobial agents demonstrated large differences between intensively reared veal calves (abundant and inconstant) and more extensively reared dairy and beef cattle (sparse and relatively stable). Using linear mixed effect models, a strong relation was found between antimicrobial treatment incidences and resistance profiles of 1,639 E. coli strains (p<0.0001) and 309 Pasteurellaceae (p≤0.012). These results indicate that a high antimicrobial selection pressure, here found to be represented by low dosages of oral prophylactic and therapeutic group medication, converts not only the commensal microbiota from the digestive tract but also the opportunistic pathogenic bacteria in the respiratory tract into reservoirs of multi-resistance.


Asunto(s)
Antibacterianos/administración & dosificación , Enfermedades de los Bovinos/tratamiento farmacológico , Cefalosporinas/administración & dosificación , Infecciones del Sistema Respiratorio/veterinaria , beta-Lactamas/administración & dosificación , Agricultura , Animales , Antibacterianos/síntesis química , Bovinos , Enfermedades de los Bovinos/epidemiología , Cefalosporinas/síntesis química , Farmacorresistencia Bacteriana , Utilización de Medicamentos , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Prevalencia , Estudios Prospectivos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/epidemiología , beta-Lactamas/síntesis química
14.
Appl Microbiol Biotechnol ; 100(11): 4885-99, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26780358

RESUMEN

The rapidly increasing problem of antimicrobial-drug resistance requires the development of new antimicrobial agents. The laccase-catalyzed amination of dihydroxy aromatics is a new and promising method to enlarge the range of currently available antibiotics. Thirty-eight potential 1,2- and 1,4-hydroquinoid laccase substrates were screened for their antibacterial and cytotoxic activity to select the best substrates for laccase-catalyzed coupling reaction resulting in potent antibacterial derivatives. As a result, methyl-1,4-hydroquinone and 2,3-dimethyl-1,4-hydroquinone were used as parent compounds and 14 novel cephalosporins, penicillins, and carbacephems were synthesized by amination with amino-ß-lactam structures. All purified products were stable in aqueous buffer and resistant to the action of ß-lactamases, and in agar diffusion and broth micro-dilution assays, they inhibited the growth of several Gram-positive bacterial strains including multidrug-resistant Staphylococcus aureus and Enterococci. Their in vivo activity and cytotoxicity in a Staphylococcus-infected, immune-suppressed mouse model are discussed.


Asunto(s)
Antiinfecciosos/síntesis química , Lacasa/metabolismo , beta-Lactamas/síntesis química , Animales , Antiinfecciosos/farmacología , Biotransformación , Catálisis , Cefalosporinas/síntesis química , Cefalosporinas/farmacología , Medios de Cultivo/química , Modelos Animales de Enfermedad , Enterococcus/efectos de los fármacos , Femenino , Bacterias Grampositivas/efectos de los fármacos , Hidroquinonas/química , Microbiología Industrial , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Penicilinas/síntesis química , Penicilinas/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus/efectos de los fármacos , beta-Lactamasas/química , beta-Lactamasas/farmacología , beta-Lactamas/farmacología
15.
Anal Biochem ; 486: 75-7, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-26142222

RESUMEN

We report on the synthesis of three nitrocefin analogues and their evaluation as substrates for the detection of ß-lactamase activity. These compounds are hydrolyzed by all four Ambler classes of ß-lactamases. Kinetic parameters were determined with eight different ß-lactamases, including VIM-2, NDM-1, KPC-2, and SPM-1. The compounds do not inhibit the growth of clinically important antibiotic-resistant gram-negative bacteria in vitro. These chromogenic compounds have a distinct absorbance spectrum and turn purple when hydrolyzed by ß-lactamases. One of these compounds, UW154, is easier to synthesize from commercial starting materials than nitrocefin and should be significantly less expensive to produce.


Asunto(s)
Cefalosporinas/síntesis química , Cefalosporinas/metabolismo , beta-Lactamasas/metabolismo , Biocatálisis , Cefalosporinas/química , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos , Hidrólisis , Cinética
18.
Prikl Biokhim Mikrobiol ; 51(6): 546-60, 2015.
Artículo en Ruso | MEDLINE | ID: mdl-26859956

RESUMEN

The currently known methods of enzymatic ß-lactam synthesis, as well as the enzymes and heterogeneous biocatalysts used for this purpose, are presented, and the published reports on advances in the field of enzymatic synthesis of selected antibiotics belonging to the groups of acidic penicillins and acidic cephalosporins are summarized in the present review. The key conditions and parameters of biocatalytic processes, such as the biocatalyst form, concentration of the precursor compounds, solvent type, pH, temperature, etc. are analyzed and compared, and guidelines for further optimization of ß-lactam synthesis are given. The present review may be of use for a wide range of readers, as well as to enzymology and biotechnology experts.


Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/química , Cefalosporinas/síntesis química , Complejos Multienzimáticos/química , Penicilina Amidasa/química , Penicilinas/síntesis química , Ácidos , Antibacterianos/biosíntesis , Proteínas Bacterianas/genética , Biocatálisis , Cefalosporinas/biosíntesis , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/genética , Escherichia coli/enzimología , Escherichia coli/genética , Expresión Génica , Concentración de Iones de Hidrógeno , Complejos Multienzimáticos/genética , Penicilina Amidasa/genética , Penicilinas/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Solventes/química , Temperatura
19.
J Environ Sci (China) ; 26(12): 2406-11, 2014 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-25499488

RESUMEN

Diisopropylthiourea (DPT), an intermediate of a widely used cephalosporin, has been found to be one of the most refractory components in cephalosporin synthesis wastewater. This compound cannot be completely removed by conventional biological processes due to its antimicrobial property. Ionizing radiation has been applied in the decomposition of refractory pollutants in recent years and has proved effective. Therefore, the decomposition of DPT by γ-irradiation was studied. The compound was irradiated at the dose of 150-2000 Gy before a change of concentration and UV absorption of the solutions was detected. Furthermore, the decomposition kinetics and radiation yield (G-value) of DPT was investigated. The results of radiation experiments on DPT-containing aqueous showed that the DPT can be effectively degraded by γ-radiation. DPT concentration decreased with increasing absorbed doses. G-values of radiolytic decomposition for DPT (20 mg/L) were 1.04 and 0.47 for absorbed doses of 150 and 2000 Gy, respectively. The initial concentration and pH of the solutions affected the degradation. As the concentration of substrate increased, the decomposition was reduced. The decrease of removal rate and radiation efficacy under alkaline condition suggested that lower pH values benefit the γ-induced degradation. UV absorption from 190 to 250 nm decreased after radiation while that from 250 to 300 nm increased, indicating the formation of by-products.


Asunto(s)
Urea/análogos & derivados , Urea/efectos de la radiación , Eliminación de Residuos Líquidos/métodos , Contaminantes Químicos del Agua/efectos de la radiación , Cefalosporinas/síntesis química , Rayos gamma , Concentración de Iones de Hidrógeno , Cinética
20.
Angew Chem Int Ed Engl ; 53(35): 9360-4, 2014 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-24989449

RESUMEN

Current methods for the detection of Mycobacterium tuberculosis (Mtb) are either time consuming or require expensive instruments and are thus are not suitable for point-of-care diagnosis. The design, synthesis, and evaluation of fluorogenic probes with high specificity for BlaC, a biomarker expressed by Mtb, are described. The fluorogenic probe CDG-3 is based on cephalosporin with substitutions at the 2 and 7 positions and it demonstrates over 120,000-fold selectivity for BlaC over TEM-1 Bla, the most common ß-lactamase. CDG-3 can detect 10 colony-forming units of the attenuated Mycobacterium bovis strain BCG in human sputum in the presence of high levels of contaminating ß-lactamases expressed by other clinically prevalent bacterial strains. In a trial with 50 clinical samples, CDG-3 detected tuberculosis with 90% sensitivity and 73% specificity relative to Mtb culture within one hour, thus demonstrating its potential as a low-cost point-of-care test for use in resource-limited areas.


Asunto(s)
Cefalosporinas/química , Colorantes Fluorescentes/química , Hidrolasas/análisis , Mycobacterium tuberculosis/aislamiento & purificación , Técnicas Bacteriológicas , Biomarcadores/análisis , Cefalosporinas/síntesis química , Colorantes Fluorescentes/síntesis química , Hidrolasas/química , Estructura Molecular , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/enzimología
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