Experimental and Therapeutic Medicine
·
2019
·Vol. 18
·期 4
·2924-2932
·
IF 1.448
Jingjing Wang,Yongzhong Ning,Shu Li,Yun Wang,Jinhua Liang,Chunming Jin,Hairun Yan,Yongcun Huang
Acinetobacter baumannii is an important cause of hospital‑acquired, multidrug‑resistant (MDR) infections occurring worldwide. Anti‑microbial combination regimens may be the only feasible treatment option for affected patients. In the present study, the efficacy of the combined therapy of meropenem with colistin, ampicillin‑sulbactam, tazobactam and vancomycin against clinical strains of MDR A. baumannii was determined. Anti‑microbial susceptibility testing was performed and resistance genes were characterized by a multiplex polymerase chain reaction (PCR)‑reverse line blot assay. The genetic background of New Delhi metallo‑β‑lactamase 1 (NDM‑1) was analysed by primer walking. The presence of NDM‑1 was detected using the modified Hodge test and the EDTA‑combined disk test. To screen for synergistic drug effects, the fractional inhibitory concentration index was calculated using a checkerboard assay. The results of the PCR as well as the sequence analyses suggested that NDM‑1 was located downstream of the ISAba125 element. In addition, a synergistic effect was determined for meropenem + vancomycin, meropenem + tazobactam and meropenem + ampicillin + sulbactam in two strains each, and in four strains for meropenem + colistin. A total of five A. baumannii strains with resistance to numerous antibiotics and carrying numerous resistance genes were identified. In the strains of A. baumannii, the NDM‑1 gene was integrated in a transposon structure with a copy of the ISAba125 insertion sequence. However, the genetic background was not identical among the different species and strains. The genetic variability of NDM‑1 may facilitate the rapid dissemination of this gene. In conclusion, meropenem may enhance the efficacy of antibiotics in A. baumannii strains with NDM‑1‑associated MDR.
研究领域:
微生物学
·
传染病学
·
临床医学
✓ 已验证
DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
·
2022
·Vol. 23
·期 5
·423-431
·
IF 3.408
Dong Jing,Liu Yanhui,Li Longxuan,Ding Yunhe,Qian Jun,Jiao Zheng
Background: Meropenem is a carbapenem antibiotic and is commonly used with other antibiotics for the treatment of bacterial infections. It is primarily eliminated renally by glomerular filtration and renal tubular secretion. Objective: This study aimed to evaluate the roles of
renal uptake and efflux transporters in the excretion of meropenem and potential drug interactions mediated by renal drug transporters. Methods: Uptake and inhibition studies were conducted in human embryonic kidney 293 cells stably transfected with Organic Anion Transporter (OAT) 1,
OAT3, Multidrug and Toxin Extrusion Protein (MATE) 1, and MATE2K, as well as membrane vesicles containing breast cancer resistance-related protein (BCRP), multidrug resistance protein 1 (MDR1), and Multidrug Resistance-associated Protein 2 (MRP2). Probenecid and piperacillin were used to assess
potential drug interactions with meropenem in rats. Results: We observed that meropenem was a low-affinity substrate of OAT1/3 and had a weak inhibitory effect on OAT1/3 and MATE2K. BCRP, MDR1, MRP2, MATE1, and MATE2K could not mediate renal excretion of meropenem. Moreover, meropenem
was not an inhibitor of BCRP, MDR1, MRP2, or MATE1. Among five tested antibiotics, moderate inhibition on OAT3-mediated meropenem uptake was observed for linezolid (IC50 value was 69.2 μM), weak inhibition was observed for piperacillin, benzylpenicillin, and tazobactam
(IC50 values were 282.2, 308.0 and 668.1 μM, respectively), and no inhibition was observed for sulbactam. Although piperacillin had a relatively high drug-drug interaction index (ratio of maximal unbound plasma concentration to IC50 was 1.42)
in vitro, no meaningful impact was reported on the pharmacokinetics of meropenem in rats. Conclusion: Our results indicated that clinically significant interactions between meropenem and these five antibiotics are low.
研究领域:
药理学
·
肾病学
·
临床药学
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2020
·
IF 4.831
De-Yun Cui,Yi Yang,Meng-Meng Bai,Jiang-Xue Han,Cong-Cong Wang,Hong-Tao Kong,Bo-Yuan Shen,Da-Chao Yan,Chun-Ling Xiao,Yi-Shuang Liu,En Zhang
New Delhi Metallo-β-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all β-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H 2 dedpa is as an efficient NDM-1 inhibitor, a series of H 2 dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC 50 values 0.06–0.94 μM. In vitro , compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae , Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time–kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n . Furthermore, compounds 6k and 6n were nonhemolytic (HC 50 > 1280 μg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn 2+ ion of the enzyme.
研究领域:
微生物学
·
药物化学
·
感染病学
✓ 已验证
DOI
高影响因子
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
·
2024
·
IF 4.9
Muchen Zhang,Siyuan Yang,Yongqing Liu,Zhiyu Zou,Yan Zhang,Yunrui Tian,Rong Zhang,Dejun Liu,Congming Wu,Jianzhong Shen,Huangwei Song,Yang Wang
The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens demands urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. Herein, we identified the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimal inhibitory concentration of meropenem against bla NDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited the potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-β-lactamases (MBLs), such as NDM and IMP, or serine β-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp. , with 32 of them obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcriptional and expressional level of the bla NDM-5 gene. Additionally, the 5-FU combined with meropenem can enhance bacterial metabolism, and stimulate the production of Reactive Oxygen Species (ROS), thereby rendering bacteria more susceptible to meropenem. This drug combination could effectively elevate the survival rate from 16.7% to 83.3% compared to meropenem monotherapy, and reduce bacteria loads in tissues in a mouse systemic infection model. Collectively, these findings reveal that the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against carbapenem-resistant bacteria infections.
研究领域:
微生物学
·
药理学
·
感染病学
✓ 已验证
DOI
高影响因子
Infection and Drug Resistance
·
2018
·
IF 3.443
Zhihui Jiang,Xianxia He,Jian Li
Purpose: The main objective of our meta-analysis was to examine the in vitro synergistic effect of meropenem-based combination therapies against Acinetobacter baumannii through a systematic review of the existing literature.Methods: An extensive search was performed with no restrictions on date of publication, language, and publication type. Our study evaluated the main conclusions drawn from various studies describing the synergistic activity of combination therapies in vitro.Results: In this review, 56 published studies were included. Our report included data on 20 types of antibiotics combined with meropenem in 1,228 Acinetobacter baumannii isolates. In time-kill studies, meropenem combined with polymyxin B and rifampicin showed synergy rates of 98.3% (95% CI, 83.7%–100.0%) and 89.4% (95% CI, 57.2%–100.0%), respectively, for Acinetobacter baumannii, modest synergy rates were found for meropenem combined with several antibiotics such as colistin and sulbactam, and no synergy effect was displayed in the combination of meropenem and ciprofloxacin, whereas in checkerboard method, the synergy rates of polymyxin B and rifampicin were 37.0% (95% CI, 0.00%–100.0%) and 56.3% (95% CI, 8.7%–97.8%), respectively.Conclusion: We found that time-kill studies generally identified the greatest synergy, while checkerboard and Etest methods yielded relatively poor synergy rates. Further well-designed in vivo studies should be carried out to confirm these findings.
✓ 已验证
DOI
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 4.833
Xiu-Fang Shi,Ming-Ming Wang,Shu-chao Huang,Jiang-Xue Han,Wen-Chao Chu,Chunling Xiao,En Zhang,Shangshang Qin
Metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containing ligands, H 2 dedpa and compound 8, were discovered with excellent activities when combined with meropenem (MEM) against MBL ( bla NDM and bla IMP )-producing clinical isolates, including Escherichia coli , Citrobacter freundii , Proteus mirabilis , Enterobacter cloacae and Klebsiella pneumoniae . In particular, these two compounds improved the activity of MEM against E. coli harboring the bla NDM-4 gene by nearly 40,960 times. H 2 dedpa (IC 50 = 0.17 ± 0.04 μM) and compound 8 (IC 50 = 0.04 ± 0.02 μM) showed higher inhibitory activity against bla NDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC 50 = 28.84 ± 0.70 μM). A sterilization kinetics experiment showed that H 2 dedpain combined with MEM could kill 99.9% of bacteria within 24 h H 2 dedpa and compound 8 are therefore promising MBL inhibitors.
✓ 已验证
DOI
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2023
·
IF 3.9
Xiaoting Dong,Wenli Liu,Yuxuan Dong,Kun Wang,Kewei Li,Liujiao Bian
Metallo-β-lactamases (MβLs) are the primary mechanism of resistance to carbapenem antibiotics. To elucidate how MβLs have evolved with the introduction and use of antibiotics, the mutation and evolution of SMB-1 from Serratia marcescens were investigated in microbial evolution plates containing discontinuous meropenem (MEM) concentration gradients. The results revealed 2-point mutations, A242G and S257R; 1 double-site mutation, C240G/E258G; and 3 frameshift mutations , M5, M12, and M13, which are all missense mutations situated at the C-terminus. Compared with that of the wild-type (WT), the minimum inhibitory concentrations (MICs) of MEM for A242G, C240G/E258G, M5, M12, and M13 increased at least 120-fold, and that of S257R increased 8-fold. The catalytic efficiency k cat /K m increased by 365% and 647%, respectively. Concerning the structural changes, the structure at the active site changed from an ordered structure to an unordered conformation. Simultaneously, the flexibility of loop 1 was enhanced. These changes increased the volume of the active site cavity; thus, this was more conducive to exposing the Zn 2+ site, facilitating substrate binding and conversion to products. In A242G, structural changes in Gly-242 can be transmitted to the active region via a network of interactions between the side chains of Gly-242 and the amino acid side chains near the active pocket. Together, these results pointed to the process of persistent drug tolerance and resistance, the SMB-1 enzyme evolved into a more exquisite structure with increased flexibility and stability, and stronger hydrolysis activity via genetic mutations and structural changes.
研究领域:
微生物学
·
药理学
·
分子生物学
·
进化生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2021
·
IF 4.155
Dongmei Zhao,Hongru Li,Chengcheng Yue,Kaili Sun,Yuanyuan Dai,Hui Zhang,Yanyan Liu,Yufeng Gao,Jiabin Li
This study investigated whether captopril can reverse drug resistance in metallo-β-lactamase (MBL)-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) and increase their sensitivity to antimicrobial agents. And also aimed to further characterize the affinity of captopril for imipenemase 4 (IMP-4) to explore the drug resistance treatment of MBL-producing bacteria. Five clinically isolated MBL-producing strains of CRKP were screened and the combined effects of captopril and meropenem were examined in vitro and in vivo to analyze whether captopril can reverse antimicrobial resistance in drug-resistant bacteria. Additionally, enzyme inhibition kinetics was analyzed to characterize the affinity of captopril for IMP-4. In MBL-producing Klebsiella pneumoniae , combined treatment with captopril significantly reduced the minimum inhibitory concentration (MIC) of carbapenems to 1 μg/mL at least, and captopril inhibited New-Delhi metallo-β-lactamase 1 (NDM-1) and IMP-4 in a concentration-dependent manner in vitro . Following the infection of Galleria mellonella by IMP-expressing bacteria, the survival rates were significantly higher in the combination treatment group than in the monotherapy groups. And the bacterial load in the combination treatment group was significantly lower than those in the monotherapy groups and IMP-4–producing bacteria were more sensitive to the combination treatment than NDM-1–producing bacteria. Additionally, enzyme inhibition kinetics firstly illustrated that the half-maximal inhibitory concentration of captopril for IMP-4 was 26.34 μM, and the dissociation constant was 37.14 μM. In brief, captopril potentiated meropenem activity and restored its efficacy against MBL-producing CRKP. Additionally, analysis of enzyme inhibition kinetics confirmed that captopril has good inhibitory effects on IMP-4 activity. Therefore, captopril or its derivatives may have clinical utility for overcoming antibiotic resistance.
研究领域:
微生物学
·
药理学
·
感染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Current Research in Microbial Sciences
·
2024
·
IF 4.8
Sirui Zhang,Jingdan Wang,Rong Yu,Haiping Liu,Shuyan Liu,Kai Luo,Jin'e Lei,Bei Han,Yanjiong Chen,Shaoshan Han,E Yang,Meng Xun,Lei Han
Although various mechanisms of carbapenem-resistance have been identified in the nosocomial pathogen Acinetobacter baumannii , the critical process of resistance evolution and the factors involved in are not well understood. Herein, we identified a universal stress protein Usp1413 which played an important role in adaptive resistance of A. baumannii to meropenem (MEM). Based on RNA-Seq and genome sequencing, Usp1413 was not only one of the most downregulated USPs, but also the bare one having mutation of tyrosine and glycine inserted at the site of 229-230 (YG229-230) under the stimulation of MEM. Deletion of Usp1413 resulted in increased MEM resistance. In addition, Usp1413 affected the bacterial abilities of biofilm formation and swarm motility, as well as helped A. baumannii response to various environmental stresses. These effects of Usp1413 were achieved by regulating its interaction proteins, within the functions of YigZ family protein, acetyltransferase, and SulP family inorganic anion transporter. The insertion mutation of YG229-230 influenced both the expression of interaction proteins and the phenotypes of bacteria. Finally, the promotor region of Usp1413 was convinced by point mutations. Overall, our findings identified the universal stress protein Usp1413 as a contributor involved in MEM adaptive resistance and responded to numerous environmental stresses. This study provides novel insights into the mechanism of universal stress proteins in participating antibiotic resistance, and affords a potential target for controlling drug resistance development in A. baumannii .
研究领域:
微生物学
·
抗药性研究
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2024
·Vol. 68
·期 3
·
IF 4.1
Xiaonan Zhang,Yan Wang,Sanwang Li,Feifan Xie,Hanxi Yi
Bacterial infections, including those caused by Pseudomonas aeruginosa, often lead to sepsis, necessitating effective antibiotic treatment like carbapenems. The key pharmacokinetic/pharmacodynamic (PK/PD) index correlated to carbapenem efficacy is the fraction time of unbound plasma concentration above the minimum inhibitory concentration (MIC) of the pathogen (%fT > MIC). While multiple targets exist, determining the most effective one for critically ill patients remains a matter of debate. This study evaluated meropenem’s bactericidal potency and its ability to combat drug resistance in Pseudomonas aeruginosa under three representative PK/PD targets: 40% fT > MIC, 100% fT > MIC, and 100% fT > 4× MIC. The hollow fiber infection model (HFIM) was constructed, validated, and subsequently inoculated with a substantial Pseudomonas aeruginosa load (1 × 108 CFU/mL). Different meropenem regimens were administered to achieve the specified PK/PD targets. At specified intervals, samples were collected from the HFIM system and subjected to centrifugation. The resulting supernatant was utilized to determine drug concentrations, while the precipitates were used to track changes in both total and drug-resistant bacterial populations over time by the spread plate method. The HFIM accurately reproduced meropenem’s pharmacokinetics in critically ill patients. All three PK/PD target groups exhibited a rapid bactericidal response within 6 h of the initial treatment. However, the 40% fT > MIC and 100% fT > MIC groups subsequently showed bacterial resurgence and resistance, whereas the 100% fT > 4× MIC group displayed sustained bactericidal activity with no evidence of drug resistance. The HFIM system revealed that maintaining 100% fT > 4× MIC offers a desirable microbiological response for critically ill patients, demonstrating strong bactericidal capacity and effective prevention of drug resistance.
研究领域:
药理学
·
感染病学
·
临床医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Zhaoyou Chu,Shu Fang,Wanyue Fu,Jun Liang,Yayun Wu,Ling Xu,Hanqing Zhang,Jiyang Wang,Haisheng Qian,Min Shao
New Delhi metallo-β-lactamase (NDM)-producing drug-resistant bacteria often form stubborn biofilms and cause severe pneumonia, resulting in conventional antibiotic failure. In this study, we developed gelatin-genipin microspheres co-loaded with EDTA and meropenem (GEM) for targeted treatment of NDM pneumonia. EDTA exerted dual functions: it chelated Zn 2+ to inactivate NDM enzyme and restore meropenem activity (FIC = 0.046875), while also disrupting bacterial biofilms through chelation. GEM microspheres enable accelerated drug release in the artificial phlegm environment. In a mouse model of NDM pneumonia, GEM microspheres can enhance the recruitment of neutrophils and M1 cells at the early stage (12 h) through bacterial clearance, modulate the secretion of interferon-γ by CD8 + T cells and natural killer cells, and reshape the pulmonary immune microenvironment. Furthermore, GEM treatment reduced pathological pulmonary immune cell infiltration and excessive inflammation at late time points (days 3-7). Taken together, GEM microspheres integrate biofilm disruption, enzyme inhibition, synergistic bactericidal effects, and immunoregulation, representing a promising strategy against NDM drug-resistant bacterial pneumonia.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL LETTERS
·
2017
·
IF 1.15
Yuan Liu,Jianye Liu,Xiaowei Li,Kunxia Zhao,Pengchun Zhang,Shuangyang Ding
A simple and sensitive method was developed and validated by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) for the determination of meropenem and ertapenem in environmental materials from dairy farms. The limits of quantification were between 1 and 20 ng/mL for the analytes in lagoon water, bedding soil, and silage. The recoveries for meropenem and ertapenem exceeded 80%. The intraday and interday precision values were less than 15% in all samples. The validated method was employed to determine the meropenem and ertapenem in environment samples obtained from dairy farms.
研究领域:
分析化学
·
环境科学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）