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1.
Qing Shao Yan Zheng Xueming Dong Prof. Kai Tang Prof. Xiaomei Yan Prof. Bengang Xing 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(33):10903-10910
Bacterial resistance to antibiotics poses a great clinical challenge in fighting serious infectious diseases due to complicated resistant mechanisms and time‐consuming testing methods. Chemical reaction‐directed covalent labeling of resistance‐associated bacterial proteins in the context of a complicated environment offers great opportunity for the in‐depth understanding of the biological basis conferring drug resistance, and for the development of effective diagnostic approaches. In the present study, three fluorogenic reagents LRBL1–3 for resistant bacteria labeling have been designed and prepared on the basis of fluorescence resonance energy transfer (FRET). The hydrolyzed probes could act as reactive electrophiles to attach the enzyme, β‐lactamase, and thus facilitated the covalent labeling of drug resistant bacterial strains. SDS electrophoresis and MALDI‐TOF mass spectrometry characterization confirmed that these probes were sensitive and specific to β‐lactamase and could therefore serve for covalent and localized fluorescence labeling of the enzyme structure. Moreover, this β‐lactamase‐induced covalent labeling provides quantitative analysis of the resistant bacterial population (down to 5 %) by high resolution flow cytometry, and allows single‐cell detection and direct observation of bacterial enzyme activity in resistant pathogenic species. This approach offers great promise for clinical investigations and microbiological research. 相似文献
2.
Yang Ding Zheng Li Chenchen Xu Wenjing Qin Qiong Wu Xuchun Wang Xiamin Cheng Lin Li Wei Huang 《Angewandte Chemie (International ed. in English)》2021,60(1):24-40
β‐Lactam antibiotics are generally perceived as one of the greatest inventions of the 20th century, and these small molecular compounds have saved millions of lives. However, upon clinical application of antibiotics, the β‐lactamase secreted by pathogenic bacteria can lead to the gradual development of drug resistance. β‐Lactamase is a hydrolase that can efficiently hydrolyze and destroy β‐lactam antibiotics. It develops and spreads rapidly in pathogens, and the drug‐resistant bacteria pose a severe threat to human health and development. As a result, detecting and inhibiting the activities of β‐lactamase are of great value for the rational use of antibiotics and the treatment of infectious diseases. At present, many specific detection methods and inhibitors of β‐lactamase have been developed and applied in clinical practice. In this Minireview, we describe the resistance mechanism of bacteria producing β‐lactamase and further summarize the fluorogenic probes, inhibitors of β‐lactamase, and their applications in the treatment of infectious diseases. It may be valuable to design fluorogenic probes with improved selectivity, sensitivity, and effectiveness to further identify the inhibitors for β‐lactamases and eventually overcome bacterial resistance. 相似文献
3.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(16):4539-4543
Antibiotic resistance has become a major challenge to public health worldwide. This crisis is further aggravated by the increasing emergence of bacterial resistance to carbapenems, typically considered as the antibiotics of last resort, which is mainly due to the production of carbapenem‐hydrolyzing carbapenemases in bacteria. Herein, the carbapenem‐based fluorogenic probe CB‐1 with an unprecedented enamine–BODIPY switch is developed for the detection of carbapenemase activity. This reagent is remarkably specific towards carbapenemases over other prevalent β‐lactamases. Furthermore, the efficient imaging of live clinically important carbapenemase‐producing organisms (CPOs) with CB‐1 demonstrates its potential for the rapid detection of antibiotic resistance and timely diagnosis of CPO infections. 相似文献
4.
A β‐Lactamase‐Imprinted Responsive Hydrogel for the Treatment of Antibiotic‐Resistant Bacteria
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Wen Li Kai Dong Prof. Jinsong Ren Prof. Xiaogang Qu 《Angewandte Chemie (International ed. in English)》2016,55(28):8049-8053
Antibiotics play important roles in infection treatment and prevention. However, the effectiveness of antibiotics is now threatened by the prevalence of drug‐resistant bacteria. Furthermore, antibiotic abuse and residues in the environment cause serious health issues. In this study, a stimuli‐responsive imprinted hydrogel was fabricated by using β‐lactamase produced by bacteria for deactivating antibiotics as the template molecule. The imprinted hydrogel could initially trap β‐lactamase excreted by drug‐resistant bacteria, thus making bacteria sensitive to antibiotics. After the bactericidal treatment, the “imprinted sites” on the hydrogel could be reversibly abolished with a temperature stimulus, which resulted in the reactivation of β‐lactamase to degrade antibiotic residues. We also present an example of the use of this antibacterial design to treat wound infection. 相似文献
5.
Engineering the Stereochemistry of Cephalosporin for Specific Detection of Pathogenic Carbapenemase‐Expressing Bacteria
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Dr. Haibin Shi Dr. Yunfeng Cheng Dr. Kyung Hyun Lee Dr. Robert F. Luo Prof. Niaz Banaei Prof. Jianghong Rao 《Angewandte Chemie (International ed. in English)》2014,53(31):8113-8116
Reported herein is the design of fluorogenic probes specific for carbapenem‐resistant Enterobacteriaceae (CRE) and they were designed based on stereochemically modified cephalosporin having a 6,7‐trans configuration. Through experiments using recombinant β‐lactamase enzymes and live bacterial species, these probes demonstrate the potential for use in the specific detection of carbapenemases, including metallo‐β‐lactamases in active bacterial pathogens. 相似文献
6.
Christopher T. Lohans H. T. Henry Chan Tika R. Malla Kiran Kumar Jos J. A. G. Kamps Darius J. B. McArdle Emma vanGroesen Mariska deMunnik Catherine L. Tooke James Spencer Robert S. Paton Jürgen Brem Christopher J. Schofield 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(7):2012-2016
Enzymes often use nucleophilic serine, threonine, and cysteine residues to achieve the same type of reaction; the underlying reasons for this are not understood. While bacterial d,d ‐transpeptidases (penicillin‐binding proteins) employ a nucleophilic serine, l,d ‐transpeptidases use a nucleophilic cysteine. The covalent complexes formed by l,d ‐transpeptidases with some β‐lactam antibiotics undergo non‐hydrolytic fragmentation. This is not usually observed for penicillin‐binding proteins, or for the related serine β‐lactamases. Replacement of the nucleophilic serine of serine β‐lactamases with cysteine yields enzymes which fragment β‐lactams via a similar mechanism as the l,d ‐transpeptidases, implying the different reaction outcomes are principally due to the formation of thioester versus ester intermediates. The results highlight fundamental differences in the reactivity of nucleophilic serine and cysteine enzymes, and imply new possibilities for the inhibition of nucleophilic enzymes. 相似文献
7.
Chunyang Chen Jan S. Kramer Steffen Brunst Ewgenij Proschak Gerhard K.E. Scriba 《Electrophoresis》2019,40(18-19):2375-2381
Generic in‐capillary as well as offline CE‐based enzyme assays were developed for serine‐β‐lactamases and metallo‐β‐lactamases. The hydrolysis of benzylpenicillin to benzylpenicilloic acid was analyzed using 100 mM sodium phosphate solution, pH 6.0, as a background electrolyte. In‐capillary assays employed an uncoated as well as a polyethylene oxide‐coated capillary, while the offline assays employing long end and short end injection were performed in an uncoated capillary. Using procaine hydrochloride or 4‐hydroxybenzoic acid as internal standard, the respective assays were validated with regard to linearity, LOD and LOQ, repeatability, precision, and accuracy. The assays were applied to the determination of the Michaelis‐Menten parameters Km and Vmax of Bacillus cereus penicillinase as well as New Delhi metallo‐β‐lactamase 1 and Verona integrin‐encoded metallo‐β‐lactamase 2. Furthermore, the inhibition of the enzymes by irreversible and competitive inhibitors was evaluated. Comparable data were obtained with all assays. The use of a simple substrate ensured broad applicability to the various types of β‐lactamases. 相似文献
8.
Daohong Liao Shaoqiang Yang Jianyu Wang Jian Zhang Benke Hong Fan Wu Prof. Dr. Xiaoguang Lei 《Angewandte Chemie (International ed. in English)》2016,55(13):4291-4295
The increase and spread of Gram‐negative bacteria that resistant are to almost all currently available β‐lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo‐β‐lactamases such as metallo‐β‐lactamase‐1 (NDM‐1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM‐1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM‐1‐expressing Gram‐negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo‐β‐lactamase inhibitors to potentiate β‐lactam antibiotics. 相似文献
9.
Dr. Kalinka Koteva Andrew M. King Prof. Alfredo Capretta Prof. Gerard D. Wright 《Angewandte Chemie (International ed. in English)》2016,55(6):2210-2212
Resistance to β‐lactam antibiotics is mediated primarily by enzymes that hydrolytically inactivate the drugs by one of two mechanisms: serine nucleophilic attack or metal‐dependent activation of a water molecule. Serine β‐lactamases are countered in the clinic by several codrugs that inhibit these enzymes, thereby rescuing antibiotic action. There are no equivalent inhibitors of metallo‐β‐lactamases in clinical use, but the fungal secondary metabolite aspergillomarasmine A has recently been identified as a potential candidate for such a codrug. Herein we report the synthesis of aspergillomarasmine A. The synthesis enabled confirmation of the stereochemical configuration of the compound and offers a route for the synthesis of derivatives in the future. 相似文献
10.
Fluorogenic Probes with Substitutions at the 2 and 7 Positions of Cephalosporin are Highly BlaC‐Specific for Rapid Mycobacterium tuberculosis Detection
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Dr. Yunfeng Cheng Dr. Hexin Xie Dr. Preeti Sule Dr. Hany Hassounah Prof. Edward A. Graviss Prof. Ying Kong Prof. Jeffrey D. Cirillo Prof. Jianghong Rao 《Angewandte Chemie (International ed. in English)》2014,53(35):9360-9364
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 β‐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 β‐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. 相似文献
11.
Monitoring Conformational Changes in the NDM‐1 Metallo‐β‐lactamase by 19F NMR Spectroscopy
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Anna M. Rydzik Jürgen Brem Sander S. van Berkel Inga Pfeffer Anne Makena Dr. Timothy D. W. Claridge Prof. Christopher J. Schofield 《Angewandte Chemie (International ed. in English)》2014,53(12):3129-3133
The New Delhi metallo‐β‐lactamase (NDM‐1) is involved in the emerging antibiotic resistance problem. Development of metallo‐β‐lactamases (MBLs) inhibitors has proven challenging, due to their conformational flexibility. Here we report site‐selective labeling of NDM‐1 with 1,1,1‐trifluoro‐3‐bromo acetone (BFA), and its use to study binding events and conformational changes upon ligand–metal binding using 19F NMR spectroscopy. The results demonstrate different modes of binding of known NDM‐1 inhibitors, including L ‐ and D ‐captopril by monitoring the changing chemical environment of the active‐site loop of NDM‐1. The method described will be applicable to other MBLs and more generally to monitoring ligand‐induced conformational changes. 相似文献
12.
《Angewandte Chemie (International ed. in English)》2017,56(14):3940-3944
A library of 2‐aminobenzimidazole derivatives was screened for the ability to suppress β‐lactam resistance in Mycobacterium smegmatis. Several non‐bactericidal compounds were identified that reversed intrinsic resistance to β‐lactam antibiotics in a manner distinct from β‐lactamase inhibitors. Activity also translates to M. tuberculosis, with a lead compound from this study potently suppressing carbenicillin resistance in multiple M. tuberculosis strains (including multidrug‐resistant strains). Preliminary mechanistic studies revealed that the lead compounds act through a mechanism distinct from that of traditional β‐lactamase inhibitors. 相似文献
13.
Muropeptides in Pseudomonas aeruginosa and their Role as Elicitors of β‐Lactam‐Antibiotic Resistance
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Dr. Mijoon Lee Supurna Dhar Dr. Stefania De Benedetti Dr. Dusan Hesek Dr. Bill Boggess Dr. Blas Blázquez Prof. Kalai Mathee Prof. Shahriar Mobashery 《Angewandte Chemie (International ed. in English)》2016,55(24):6882-6886
Muropeptides are a group of bacterial natural products generated from the cell wall in the course of its turnover. These compounds are cell‐wall recycling intermediates and are also involved in signaling within the bacterium. However, the identity of these signaling molecules remains elusive. The identification and characterization of 20 muropeptides from Pseudomonas aeruginosa is described. The least abundant of these metabolites is present at 100 and the most abundant at 55,000 molecules per bacterium. Analysis of these muropeptides under conditions of induction of resistance to a β‐lactam antibiotic identified two signaling muropeptides (N‐acetylglucosamine‐1,6‐anhydro‐N‐acetylmuramyl pentapeptide and 1,6‐anhydro‐N‐acetylmuramyl pentapeptide). Authentic synthetic samples of these metabolites were shown to activate expression of β‐lactamase in the absence of any β‐lactam antibiotic, thus indicating that they serve as chemical signals in this complex biochemical pathway. 相似文献
14.
Enzyme‐Responsive Polymeric Vesicles for Bacterial‐Strain‐Selective Delivery of Antimicrobial Agents
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Yamin Li Dr. Guhuan Liu Xiaorui Wang Dr. Jinming Hu Prof. Dr. Shiyong Liu 《Angewandte Chemie (International ed. in English)》2016,55(5):1760-1764
Antimicrobial resistance poses serious public health concerns and antibiotic misuse/abuse further complicates the situation; thus, it remains a considerable challenge to optimize/improve the usage of currently available drugs. We report a general strategy to construct a bacterial strain‐selective delivery system for antibiotics based on responsive polymeric vesicles. In response to enzymes including penicillin G amidase (PGA) and β‐lactamase (Bla), which are closely associated with drug‐resistant bacterial strains, antibiotic‐loaded polymeric vesicles undergo self‐immolative structural rearrangement and morphological transitions, leading to sustained release of antibiotics. Enhanced stability, reduced side effects, and bacterial strain‐selective drug release were achieved. Considering that Bla is the main cause of bacterial resistance to β‐lactam antibiotic drugs, as a further validation, we demonstrate methicillin‐resistant S. aureus (MRSA)‐triggered release of antibiotics from Bla‐degradable polymeric vesicles, in vitro inhibition of MRSA growth, and enhanced wound healing in an in vivo murine model. 相似文献
15.
A New Mechanism for β‐Lactamases: Class D Enzymes Degrade 1β‐Methyl Carbapenems through Lactone Formation
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Dr. Christopher T. Lohans Emma van Groesen Kiran Kumar Catherine L. Tooke Dr. James Spencer Prof. Dr. Robert S. Paton Dr. Jürgen Brem Prof. Dr. Christopher J. Schofield 《Angewandte Chemie (International ed. in English)》2018,57(5):1282-1285
β‐Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl‐enzyme intermediate. We show that class D β‐lactamases also degrade clinically used 1β‐methyl‐substituted carbapenems through the unprecedented formation of a carbapenem‐derived β‐lactone. β‐Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl‐enzyme intermediate. The carbapenem‐derived lactone products inhibit both serine β‐lactamases (particularly class D) and metallo‐β‐lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required. 相似文献
16.
An Antibacterial β‐Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis
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Dr. Johannes Lehmann Dr. Tan‐Yun Cheng Dr. Anup Aggarwal Dr. Annie S. Park Dr. Evelyn Zeiler Dr. Ravikiran M. Raju Dr. Tatos Akopian Dr. Olga Kandror Prof. Dr. James C. Sacchettini Prof. Dr. D. Branch Moody Prof. Dr. Eric J. Rubin Prof. Dr. Stephan A. Sieber 《Angewandte Chemie (International ed. in English)》2018,57(1):348-353
The spread of antibiotic resistance is a major challenge for the treatment of Mycobacterium tuberculosis infections. In addition, the efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis, leading to rapid cell death. Inspired by this mechanism, we exploited β‐lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β‐lactones, we found one hit with potent anti‐mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation through enzyme assays and customized 13C metabolite profiling showed that both targets are functionally impaired by the β‐lactone. Co‐administration with front‐line antibiotics enhanced the potency against M. tuberculosis by more than 100‐fold, thus demonstrating the therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases. 相似文献
17.
Christopher Selleck Prof. James A. Larrabee Assoc. Prof. Jeffrey Harmer Assoc. Prof. Luke W. Guddat Dr. Nataša Mitić Waleed Helweh Prof. David L. Ollis Dr. Whitney R. Craig Prof. David L. Tierney Dr. Marcelo Monteiro Pedroso Prof. Gerhard Schenk 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(49):17704-17714
Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo‐β‐lactamases (MBL) have evolved to inactivate most of the commonly used β‐lactam antibiotics. AIM‐1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs. Unlike other MBLs it appears that AIM‐1 has two avenues available for the turnover of the substrate nitrocefin, distinguished by the identity of the rate‐limiting step. This observation may be relevant with respect to inhibitor design for this group of enzymes as it demonstrates that at least some MBLs are very flexible in terms of interactions with substrates and possibly inhibitors. 相似文献
18.
Dr. Tomohiro Doura Dr. Mako Kamiya Dr. Fumiaki Obata Dr. Yoshifumi Yamaguchi Dr. Takeshi Y. Hiyama Takashi Matsuda Prof. Akiyoshi Fukamizu Prof. Masaharu Noda Prof. Masayuki Miura Prof. Yasuteru Urano 《Angewandte Chemie (International ed. in English)》2016,55(33):9620-9624
The LacZ gene, which encodes Escherichia coli β‐galactosidase, is widely used as a marker for cells with targeted gene expression or disruption. However, it has been difficult to detect lacZ‐positive cells in living organisms or tissues at single‐cell resolution, limiting the utility of existing lacZ reporters. Herein we present a newly developed fluorogenic β‐galactosidase substrate suitable for labeling live cells in culture, as well as in living tissues. This precisely functionalized fluorescent probe exhibited dramatic activation of fluorescence upon reaction with the enzyme, remained inside cells by anchoring itself to intracellular proteins, and provided single‐cell resolution. Neurons labeled with this probe preserved spontaneous firing, which was enhanced by application of ligands of receptors expressed in the cells, suggesting that this probe would be applicable to investigate functions of targeted cells in living tissues and organisms. 相似文献
19.
Anthony M. Haag Audrie M. Medina Ariel E. Royall Norbert K. Herzog David W. Niesel 《Journal of mass spectrometry : JMS》2013,48(6):732-739
Antibiotic resistance is a growing problem worldwide. For this reason, clinical laboratories often determine the susceptibility of the bacterial isolate to a number of different antibiotics in order to establish the most effective antibiotic for treatment. Unfortunately, current susceptibility assays are time consuming. Antibiotic resistance often involves the chemical modification of an antibiotic to an inactive form by an enzyme expressed by the bacterium. Selected reaction monitoring (SRM) has the ability to quickly monitor and identify these chemical changes in an unprecedented time scale. In this work, we used SRM as a technique to determine the susceptibility of several different antibiotics to the chemically modifying enzymes β‐lactamase and chloramphenicol acetyltransferase, enzymes used by bacteria to confer resistance to major classes of commonly used antibiotics. We also used this technique to directly monitor the effects of resistant bacteria grown in a broth containing a specific antibiotic. Because SRM is highly selective and can also identify chemical changes in a multitude of antibiotics in a single assay, SRM has the ability to detect organisms that are resistant to multiple antibiotics in a single assay. For these reasons, the use of SRM greatly reduces the time it takes to determine the susceptibility or resistance of an organism to a multitude of antibiotics by eliminating the time‐consuming process found in other currently used methods. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
20.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(24):6990-6994
Antimicrobial resistance (AMR), the ability of a bacterial species to resist the action of an antimicrobial drug, has been on the rise due to the widespread use of antimicrobial agents. Per the World Health Organization, AMR has an estimated annual cost of USD 34 billion in the US and is predicted to be the number one cause of death worldwide by 2050. One way AMR bacteria can spread, and by which individuals can contract AMR infections, is through contaminated water. Monitoring AMR bacteria in the environment currently requires that samples be transported to a central laboratory for slow and labor intensive tests. We have developed an inexpensive assay using paper‐based analytical devices (PADs) that can test for the presence of β‐lactamase‐mediated resistance. To demonstrate viability, the PAD was used to detect β‐lactam resistance in wastewater and sewage and identified resistance in individual bacterial species isolated from environmental water sources. 相似文献