An in silico Approach to Identify Potential NDM-1 Inhibitors to Fight Multidrug Resistant Superbugs

2019 ◽  
Vol 14 (1) ◽  
pp. 79-84
Author(s):  
Seema Barman ◽  
Bonashree Phukan ◽  
Partha Sarathi Borah ◽  
Minakshi Puzari ◽  
Mohan Sharma ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Docking ◽  
Treatment Options ◽  
Quantitative Structure Activity Relationship ◽  
Multidrug Resistant ◽  
New Delhi ◽  
Gram Negative Bacteria ◽  
Global Threat ◽  
Relationship Assessment ◽  
Plant Sources

Background: Antibiotic resistance is a global threat and the emergence of Multi-Drug Resistant (MDR) bacteria compromises the treatment options, limiting the number of available drugs. New Delhi Metallo-beta-lactamase-1 (NDM-1) mediated drug resistance is one of the mechanisms associated with multidrug resistance. </P><P> Objective: In our study, reverse chemogenomics technique was applied for identification of potential NDM-1 inhibitors from plant sources to combat the issue of drug resistance in Gram-negative bacteria. </P><P> Method: Computational methodologies were employed to understand and validate the molecular interaction between the target protein and the ligands. A total of 22 plant-based compounds were screened for inhibitory activity against NDM-1 through subsequent comparative molecular docking. The compounds were passed through Lipinski filter and ADME-Tox filter, which represent an important part of drug discovery. </P><P> Result: On the basis of optimum molecular docking values, Garcinol was recognized as the most potential NDM-1 inhibitor. However, in Quantitative-Structure Activity Relationship assessment, Ajugasterone-C showed the least value of minimum inhibitory concentration. Most of the compounds were found to comply with Lipinski rule of 5 and showed good results in ADME-Tox filtration. </P><P> Conclusion: Garcinol and Ajugasterone-C were found to possess drug like characteristics and can act as potential NDM-1 inhibitors.

scholarly journals Case Commentary: the Need for Cefiderocol Is Clear, but Are the Supporting Clinical Data?

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Ryan K. Shields
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Salvage Therapy ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Potential Utility ◽  
Gram Negative

ABSTRACT Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded in vitro activity against multidrug-resistant Gram-negative bacteria. In two challenging cases reported here, cefiderocol shows potential utility as salvage therapy against difficult-to-treat pathogens with limited or no treatment options; however, two multicenter, randomized clinical trials have yielded mixed results among cefiderocol-treated patients. Taken together, clinicians must balance a clear need for cefiderocol in clinical practice with the uncertainties that have stemmed from the available data.

scholarly journals Assessment of Ceftazidime-Avibactam 30/20-μg Disk, Etest versus Broth Microdilution Results When Tested against Enterobacterales Clinical Isolates

2022 ◽  
Author(s):  
Renru Han ◽  
Xuelin Yang ◽  
Yang Yang ◽  
Yan Guo ◽  
Dandan Yin ◽  
...  
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Broth Microdilution ◽  
Gram Negative ◽  
Extended Spectrum ◽  
The World ◽  
Multidrug Resistant Pathogens ◽  
Combinational Therapies

Multidrug-resistant Gram-negative bacteria, especially for extended-spectrum β-lactamases-producing and carbapenemase-producing Enterobacterales , are disseminating rapidly around the world. Treatment options for these infections are limited, which prompt the development of novel or combinational therapies to combat the infections caused by multidrug-resistant pathogens.

scholarly journals EVALUATION OF EFFLUX PUMP ACTIVITY AND BIOFILM FORMATION IN MULTIDRUG RESISTANT KLEBSIELLA PNEUMONIAE ISOLATES IN TANTA, EGYPT

2021 ◽  
Vol 12 (3) ◽  
pp. 1-5
Author(s):  
Tarek El-Said El-Banna ◽  
Fatma Ibrahim Sonbol ◽  
Heba M El-Dawy ◽  
Lamiaa A Al-Madboly
Keyword(s):  
Drug Resistance ◽  
Klebsiella Pneumoniae ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
High Morbidity ◽  
Biochemical Tests ◽  
Antibiotic Resistance Profile ◽  
Pump Activity

Nosocomial and community acquired infections that caused by multidrug-resistant (MDR) Klebsiella pneumoniae isolates are widespread recently resulting in high morbidity and mortality due to limited number of treatment options with effective antibiotics. The aim of this study is to evaluate the antibiotic resistance profile, biofilm formation and efflux pump activity of MDR K. pneumoniae isolates collected from different hospitals in Tanta, Egypt. A total of 70 K. pneumoniae isolates characterized by standard biochemical tests and confirmed by MALDI-TOF/MS were screened for antibiotic susceptibility, efflux pump activity and biofilm formation. Isolates displayed high resistance to penicillins, cephalosporins, trimethoprim-sulfamethoxazole and the majority of tested fluoro/-quinolones and decreased resistance to imipenem, amikacin, chloramphenicol, tigecycline and colistin. Out of 70 K. pneumoniae isolates, 2 isolates exhibited Pan Drug-Resistance (PDR) profile while 57 (81.4%) and 11 (15.7%) exhibited MDR and Extensively drug-resistance (XDR) profiles, respectively. Sixty-four (91.4%) isolates exhibited efflux pump activity while all tested isolates had the ability to form biofilm with varied degrees as 40 (57.1%), 26 (37.1%), and 4 (5.7%) isolates were strong, moderate and weak biofilm producers, respectively. Also, a strong relation between efflux pump activity and biofilm formation per isolate was detected. In conclusion, Multidrug resistance, biofilm formation and efflux pump capabilities in K. pneumoniae have serious public health implications in the management and control of infections caused by this bacterium. Therefore, a multifaceted approach and precise planning are recommended in controlling these infections

scholarly journals Cefiderocol, a new antibiotic against multidrug-resistant Gram-negative bacteria

2021 ◽  
Vol 34 (Suppl 1) ◽  
pp. 41-43
Author(s):  
José Tiago Silva ◽  
Francisco López-Medrano
Keyword(s):  
Bacterial Pneumonia ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Tract Infections ◽  
Transport Channels ◽  
Hospital Acquired

Cefiderocol is a novel catechol-substituted siderophore cephalosporin that binds to the extracellular free iron, and uses the bacterial active iron transport channels to penetrate in the periplasmic space of Gram-negative bacteria (GNB). Cefiderocol overcomes many resistance mechanisms of these bacteria. Cefiderocol is approved for the treatment of complicated urinary tract infections, hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in the case of adults with limited treatment options, based on the clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In the CREDIBLE-CR trial, a higher all-cause mortality was observed in the group of patients who received cefiderocol, especially those with severe infections due to Acinetobacter spp. Further phase III clinical studies are necessary in order to evaluate cefiderocol´s efficacy in the treatment of serious infections.

scholarly journals Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

2021 ◽  
Vol 14 (10) ◽  
pp. 1051
Author(s):  
Onat Kadioglu ◽  
Mohamed Elbadawi ◽  
Edmond Fleischer ◽  
Thomas Efferth
Keyword(s):  
Drug Resistance ◽  
Molecular Docking ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Hek293 Cells ◽  
Transfected Cells ◽  
Anthracycline Resistance ◽  
Approved Drugs ◽  
Sensitizing Effect

Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.

scholarly journals Antibiotic Susceptibility of NDM-Producing Enterobacterales Collected in the United States in 2017 and 2018

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Joseph D. Lutgring ◽  
Rocío Balbuena ◽  
Natashia Reese ◽  
Sarah E. Gilbert ◽  
Uzma Ansari ◽  
...  
Keyword(s):  
United States ◽  
Antibiotic Susceptibility ◽  
Treatment Options ◽  
The United States ◽  
Multidrug Resistant ◽  
New Delhi ◽  
Drug Resistant ◽  
Carbapenem Resistant ◽  
Extensively Drug Resistant

ABSTRACT The treatment of infections caused by carbapenem-resistant Enterobacterales, especially New Delhi metallo-β-lactamase (NDM)-producing bacteria, is challenging. Although less common in the United States than some other carbapenemase producers, NDM-producing bacteria are a public health threat due to the limited treatment options available. Here, we report on the antibiotic susceptibility of 275 contemporary NDM-producing Enterobacterales collected from 30 U.S. states through the Centers for Disease Control and Prevention’s Antibiotic Resistance Laboratory Network. The aims of the study were to determine the susceptibility of these isolates to 32 currently available antibiotics using reference broth microdilution and to explore the in vitro activity of 3 combination agents that are not yet available. Categorical interpretations were determined using Clinical and Laboratory Standards Institute (CLSI) interpretive criteria. For agents without CLSI criteria, Food and Drug Administration (FDA) interpretive criteria were used. The percentage of susceptible isolates did not exceed 90% for any of the FDA-approved antibiotics tested. The antibiotics with breakpoints that had the highest in vitro activity were tigecycline (86.5% susceptible), eravacycline (66.2% susceptible), and omadacycline (59.6% susceptible); 18.2% of isolates were susceptible to aztreonam. All NDM-producing isolates tested were multidrug resistant, and 116 isolates were extensively drug resistant (42.2%); 207 (75.3%) isolates displayed difficult-to-treat resistance. The difficulty in treating infections caused by NDM-producing Enterobacterales highlights the need for containment and prevention efforts to keep these infections from becoming more common.

scholarly journals Efficacy of colistin in multidrug-resistant neonatal sepsis: experience from a tertiary care center in Karachi, Pakistan

2020 ◽  
Vol 105 (9) ◽  
pp. 830-836 ◽  
Author(s):  
Gul Ambreen ◽  
Muhammad Sohail Salat ◽  
Kashif Hussain ◽  
Syed Shamim Raza ◽  
Umer Ali ◽  
...  
Keyword(s):  
Neonatal Intensive Care ◽  
Care Center ◽  
Treatment Options ◽  
Tertiary Care ◽  
Multidrug Resistant ◽  
University Hospital ◽  
Electrolyte Imbalance ◽  
High Morbidity ◽  
Gram Negative Bacteria ◽  
Record Review

ObjectiveInfections with multidrug-resistant organisms (MDROs) such as Gram-negative bacteria have high morbidity and mortality with limited treatment options. Colistin, an antibiotic active against MDRO, was rarely used due to frequent adverse effects, but its use has now been recommended among adults. In this study, we determined the efficacy of colistin for the treatment of sepsis in neonates.Design/setting/patients/outcomesWe conducted a retrospective record review of all neonates admitted to the neonatal intensive care unit of Aga Khan University Hospital, Karachi, Pakistan, between June 2015 and June 2018, who had sepsis and received colistin by intravenous, inhalation and/or intrathecal routes. Predictors of colistin efficacy, for neonatal survival and microbial clearance, were assessed using multiple logistic regression.Results153 neonates received colistin; 120 had culture-proven sepsis; and 93 had MDR-GNB (84 colistin-sensitive). 111 (72.5%) neonates survived and were discharged from hospital; 82.6% had microbial clearance. Neonates with colistin-sensitive bacteria (adjusted OR (AOR)=3.2, 95% CI 2.8 to 4.0), and those in which colistin therapy started early (AOR=7.2, 95% CI 3.5 to 13.6) were more likely to survive. Neonates with increased gestational age (AOR=1.9, 95% CI 1.5 to 3.0), higher weight (AOR=5.4, 95% CI 3.3 to 11.8) and later onset of sepsis (AOR=4.3, 95% CI 2.0 to 9.0) had higher survival. Adverse events included nephrotoxicity in 5.2%; 13.7% developed seizures and 18.3% had electrolyte imbalance.ConclusionsColistin therapy was associated with survival among neonates suffering from MDR-GNB sepsis. The frequency of side effects was moderate.

scholarly journals Evaluation of Intraventricular/Intrathecal Antimicrobial Therapy in the Treatment of Nosocomial Meningitis Caused by Multidrug-Resistant Gram-Negative Bacteria after Central Nervous System Surgery

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Nagehan Didem Sari ◽  
Sevim Baltali ◽  
Istemi Serin ◽  
Veysel Antar
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Success ◽  
Day Treatment ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Mortality And Morbidity ◽  
Postoperative Meningitis

Introduction. Postoperative meningitis (POM) is an infection with high mortality and morbidity following central nervous system surgery due to trauma or tumor. Intrathecal/intraventricular (IT/IVT) antibiotic administrations have been considered as the last treatment options for multidrug-resistance (MDR) Gram-negative bacteria that do not respond to intravenous (IV) regimens. IT/IVT can bypass the blood-brain barrier, obtain a more effective antibiotic concentration in CSF, and reduce systemic side effects. We aimed to determine the characteristics of postoperative patients who were diagnosed with MDR POM during follow-up in our intensive care unit (ICU). Material and Methods. In this study, POM patients who were followed up in ICU after the central nervous system intervention between January 2016 and December 2019 and whose MDR Gram-negative bacteria were isolated from CSF were evaluated. As soon as the patients were diagnosed with POM, a catheter was inserted and treatment was started. Results. Microbiological eradication was achieved in 3 ± 0.8 days with 30 mg/day amikacin treatment in POM due to K. pneumoniae and 3.7 ± 1.95 days with colistin sodium 10 mg/day treatment in POM due to A. baumannii via IT/IVT catheter. IT/IVT treatment was utilized for a median of 10 days and continued until the defined cure criteria were achieved. While cure was achieved in 6 of 14 POM cases, 8 of them were exitus. Discussion and Conclusion. To avoid the severe consequences of postoperative meningitis, acting fast and adding IT/IVT methods to parenteral administration routes by considering the distribution of MDR microorganisms within the hospital while planning effective treatment will increase the clinical success.

scholarly journals Intra-pleural colistin methanesulfonate therapy for pleural infection caused by carbapenem-resistant Acinetobacter baumannii: a successful case report

2014 ◽  
Vol 6 (3) ◽  
Author(s):  
Muhammad Asim Rana ◽  
Basheer Abd El Rahaman ◽  
Ahmed Fouad Mady ◽  
Mohammed Al Odat ◽  
Abdurehman Al Harthy ◽  
...  
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Antimicrobial Treatment ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Unsuccessful Treatment ◽  
Successful Case ◽  
Pleural Infection ◽  
Colistin Methanesulfonate

Infections caused by carbapenem-resistant, Gram-negative bacteria are an increasing clinical challenge, since the antimicrobial treatment options are often limited to colistin methanesulfonate. No data are available regarding the pharmacokinetics of colistin in pleural fluid. We report the case of a 92-year old man with ventilator-associated pneumonia and pleurisy caused by <em>Acinetobacter</em> <em>baumannii</em> and <em>Escherichia coli</em>, which were both multidrug-resistant. After an unsuccessful treatment with intravenous colistin methanesulfonate and imipenem-cilastatin, the addition of intra-pleural colistin methanesulfonate to the intravenous treatment led to a prompt clinical, radiological and microbiological resolution. This is the first report of a successful use of intra-pleural colistin in the literature. The intra-pleural colistin therapy should be considered in selected cases of pleurisy caused by multi-resistant Gram-negative bacteria.

scholarly journals The Characterization of OXA-232 Carbapenemase-Producing ST437 Klebsiella pneumoniae in China

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Xingbei Weng ◽  
Qiucheng Shi ◽  
Sheng Wang ◽  
Yubo Shi ◽  
Dinghe Sun ◽  
...  
Keyword(s):  
Public Health ◽  
High Risk ◽  
Klebsiella Pneumoniae ◽  
Clonal Complex ◽  
Multidrug Resistant ◽  
New Delhi ◽  
Carbapenem Resistant ◽  
The World ◽  
Global Threat

Carbapenem-resistant Klebsiella pneumoniae (CRKP) was epidemic around the world and become a global threat to public health. The most important carbapenem-resistant mechanism is producing carbapenemases, especially Klebsiella pneumoniae carbapenemase (KPC), which is prevalent in the international clonal complex CC11. The high-risk multidrug-resistant CC11 is widespread worldwide, and KPC-producing and (New Delhi metallo) NDM-producing strains had been reported in this clonal complex before; moreover, cases with the CC11 strain faced more severe forms of drug resistance and treatment challenges than other clonal complexes. In this study, we identified an OXA-232-producing ST437 Klebsiella pneumoniae isolate in China, which belonged to CC11. The isolate was resistant to β-lactams, aminoglycosides, and fluoroquinolones but susceptible to fosfomycin, tigecycline, and colistin. The blaOXA-232 gene was located on a 6141 bp ColKP3-type nonconjugative plasmid, and the plasmid was transformed by chemical transformation successfully. This is the first report of OXA-232-producing ST437 K. pneumoniae in China, a new clone of high-risk multidrug-resistant CC11.

Sign in / Sign up

Export Citation Format

Share Document