scholarly journals Drug resistant gut bacteria mimic a host mechanism for anticancer drug clearance

2019 ◽  
Author(s):  
Peter Spanogiannopoulos ◽  
Patrick H. Bradley ◽  
Jonathan Melamed ◽  
Ysabella Noelle Amora Malig ◽  
Kathy N. Lam ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Drug Disposition ◽  
Transcriptional Profiling ◽  
Drug Efficacy ◽  
Drug Clearance ◽  
Gut Bacteria ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Bacterial Strains

Microbiome surveys indicate that pharmaceuticals are the top predictor of inter-individual variations in gut microbial community structure1, consistent with in vitro evidence that non-antibiotic (i.e. host-targeted) drugs inhibit gut bacterial growth2and are subject to extensive metabolism by the gut microbiome3,4. In oncology, bacterial metabolism has been implicated in both drug efficacy5,6and toxicity7,8; however, the degree to which bacterial sensitivity and metabolism can be driven by conserved pathways also found in mammalian cells remains poorly understood. Here, we show that anticancer fluoropyrimidine drugs broadly inhibit the growth of diverse gut bacterial strains. Media supplementation, transcriptional profiling (RNA-seq), and bacterial genetics implicated pyrimidine metabolism as a key target in bacteria, as in mammalian cells. Drug resistant bacteria metabolized 5FU to its inactive metabolite dihydrofluorouracil (DHFU) mimicking the major host pathway for drug clearance. Functional orthologs of the bacterial operon responsible (preTA) are widespread across human gut bacteria from the Firmicutes and Proteobacteria phyla. The observed conservation of both the targets and pathways for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug disposition9, efficacy, and side effect profiles.

scholarly journals Imaging Sensitive and Drug-Resistant Bacterial Infection with [11C]-TMP: In Vitro and First-in-Human Evaluation

2021 ◽  
Author(s):  
Iris K Lee ◽  
Daniel A Jacome ◽  
Joshua K Cho ◽  
Vincent Tu ◽  
Anthony Young ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Mammalian Cells ◽  
Bacterial Infections ◽  
The Body ◽  
Response Monitoring ◽  
Drug Resistant ◽  
Bacterial Strains ◽  
Critical Question ◽  
In Vitro Uptake

Recently, several molecular imaging strategies have developed to image bacterial infections in humans. Nuclear approaches, specifically positron emission tomography (PET), affords sensitive detection and the ability to non-invasively locate infections deep within the body. Two key radiotracer classes have arisen: metabolic approaches targeting bacterial specific biochemical transformations, and antibiotic-based approaches that have inherent selectivity for bacteria over mammalian cells. A critical question for clinical application of antibiotic radiotracers is whether resistance to the template antibiotic abrogates specific uptake, thus diminishing the predictive value of the diagnostic test. We recently developed small-molecule PET radiotracers based on the antibiotic trimethoprim (TMP), including [11C]-TMP, and have shown their selectivity for imaging bacteria in preclinical models. Here, we measure the in vitro uptake of [11C]-TMP in pathogenic susceptible and drug-resistant bacterial strains. Both resistant and susceptible bacteria showed similar in vitro uptake, which led us to perform whole genome sequencing of these isolates to identify the mechanisms of TMP resistance that permit retained radiotracer binding. By interrogating these isolate genomes and a broad panel of previously sequenced strains, we reveal mechanisms where uptake or binding of TMP radiotracers can potentially be maintained despite the annotation of genes conferring antimicrobial resistance. Finally, we present several examples of patients with both TMP-sensitive and drug-resistant infections in our first-in-human experience with [11C]-TMP. This work underscores the ability of an antibiotic radiotracer to image bacterial infection in patients, which may allow insights into human bacterial pathogenesis, infection diagnosis, and antimicrobial response monitoring.

scholarly journals ANTIBACTERIAL PHOTODYNAMIC THERAPEUTIC STUDIES OF METALLATED PORPHYRIN AGAINST CHRONIC WOUND COLONISING BACTERIAL ISOLATES

2021 ◽  
Vol 46 (2) ◽  
Author(s):  
O. B Daramola ◽  
A. A Olajide ◽  
N Torimiro ◽  
R. C George
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Chronic Wound ◽  
Antimicrobial Activities ◽  
Diffusion Method ◽  
In Vitro Toxicity ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Bacterial Strains

Wound infections have become life threatening as a result of treatment failures caused by multi-drug resistant pathogens. The search for newer compounds potent against antibiotic resistant bacteria associated with wounds is crucial. Hence this study investigated the application of antibacterial photodynamic therapy using meso tetra-(4-phenyl) porphyrin (TPP), metallated with zinc, tin and silver (ZnTPP, SnTPP and AgTPP), meso tetra-(4-sulphonatephenyl) porphyrin (TPPS) and the corresponding metallo meso tetra-(4-sulphonatephenyl) porphyrin (MTPPS) as photosensitizers. The in-vitro toxicity and photo-toxicity properties on four chronic wound colonizing multi-drug resistant bacterial strains: Staphylococcus aureus, Klebsiella sp., Proteus sp., and Escherichia coli were assessed using agar well diffusion method. Photo-toxicity of the compounds was investigated using 100 Watt tungsten lamp. Inhibitory activity of porphyrins tested against these bacterial strains showed Staphylococcus aureus to have both lowest (11±0.0 mm) and highest (33±1.1 mm) susceptibility to SnTPPS and ZnTPPS respectively. The sequence of data also showed appreciable improvement in the antimicrobial activities of five metalloporphyrins (SnTPP, AgTPP, ZnTPPS, SnTPPS and AgTPPS) exposed to light rays than when tested against bacterial strains in dark condition. ZnTPPS exhibited the best activity with improved photo-toxic activities against all bacterial strains (Staphylococcus aureus 33±1.1 mm, Klebsiella sp. 32±0.7 mm, Proteus sp. 28±0.7 mm and Escherichia coli 30±1.4 mm) examined in this study.

scholarly journals Bacteriophages to Control Multi-Drug Resistant Enterococcus faecalis Infection of Dental Root Canals

2021 ◽  
Vol 9 (3) ◽  
pp. 517
Author(s):  
Mohamed El-Telbany ◽  
Gamal El-Didamony ◽  
Ahmed Askora ◽  
Eman Ariny ◽  
Dalia Abdallah ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Root Canal ◽  
Phage Therapy ◽  
Ex Vivo ◽  
Burst Size ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Range Analysis ◽  
Root Canals

Phage therapy is an alternative treatment to antibiotics that can overcome multi-drug resistant bacteria. In this study, we aimed to isolate and characterize lytic bacteriophages targeted against Enterococcus faecalis isolated from root canal infections obtained from clinics at the Faculty of Dentistry, Ismalia, Egypt. Bacteriophage, vB_ZEFP, was isolated from concentrated wastewater collected from hospital sewage. Morphological and genomic analysis revealed that the phage belongs to the Podoviridae family with a linear double-stranded DNA genome, consisting of 18,454, with a G + C content of 32.8%. Host range analysis revealed the phage could infect 10 of 13 E. faecalis isolates exhibiting a range of antibiotic resistances recovered from infected root canals with efficiency of plating values above 0.5. One-step growth curves of this phage showed that it has a burst size of 110 PFU per infected cell, with a latent period of 10 min. The lytic activity of this phage against E. faecalis biofilms showed that the phage was able to control the growth of E. faecalis in vitro. Phage vB_ZEFP could also prevent ex-vivo E. faecalis root canal infection. These results suggest that phage vB_ZEFP has potential for application in phage therapy and specifically in the prevention of infection after root canal treatment.

scholarly journals Distinct Chemistries Define the Diverse Biological Effects of Plasma Activated Water Generated with Spark and Glow Plasma Discharges

2021 ◽  
Vol 11 (3) ◽  
pp. 1178
Author(s):  
Evanthia Tsoukou ◽  
Maxime Delit ◽  
Louise Treint ◽  
Paula Bourke ◽  
Daniela Boehm
Keyword(s):  
Mammalian Cells ◽  
Biomedical Application ◽  
Biological Effects ◽  
Mode Of Delivery ◽  
Chemical Species ◽  
Resistant Bacteria ◽  
Cytotoxic Activities ◽  
Promising Alternative ◽  
Plasma Activated Water

The spread of multidrug-resistant bacteria poses a significant threat to human health. Plasma activated liquids (PAL) could be a promising alternative for microbial decontamination, where different PAL can possess diverse antimicrobial efficacies and cytotoxic profiles, depending on the range and concentration of their reactive chemical species. In this research, the biological activity of plasma activated water (PAW) on different biological targets including both microbiological and mammalian cells was investigated in vitro. The aim was to further an understanding of the specific role of distinct plasma reactive species, which is required to tailor plasma activated liquids for use in applications where high antimicrobial activity is required without adversely affecting the biology of eukaryotic cells. PAW was generated by glow and spark discharges, which provide selective generation of hydrogen peroxide, nitrite and nitrate in the liquid. The PAW made by either spark or glow discharges showed similar antimicrobial efficacy and stability of activity, despite the very different reactive oxygen species (ROS) and reactive nitrogen species profiles (RNS). However, different trends were observed for cytotoxic activities and effects on enzyme function, which were translated through the selective chemical species generation. These findings indicate very distinct mechanisms of action which may be exploited when tailoring plasma activated liquids to various applications. A remarkable stability to heat and pressure was noted for PAW generated with this set up, which broadens the application potential. These features also suggest that post plasma modifications and post generation stability can be harnessed as a further means of modulating the chemistry, activity and mode of delivery of plasma functionalised liquids. Overall, these results further understanding on how PAL generation may be tuned to provide candidate disinfectant agents for biomedical application or for bio-decontamination in diverse areas.

scholarly journals Agreement Assessment of Tigecycline Susceptibilities Determined by the Disk Diffusion and Broth Microdilution Methods among Commonly Encountered Resistant Bacterial Isolates: Results from the TigecyclineIn VitroSurveillance in Taiwan (TIST) Study, 2008 to 2010

2011 ◽  
Vol 56 (3) ◽  
pp. 1414-1417 ◽  
Author(s):  
Jien-Wei Liu ◽  
Wen-Chien Ko ◽  
Cheng-Hua Huang ◽  
Chun-Hsing Liao ◽  
Chin-Te Lu ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Total Error ◽  
Error Rates ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Broth Microdilution ◽  
Content Type ◽  
E Coli ◽  
Drug Resistant Bacteria

ABSTRACTThe TigecyclineIn VitroSurveillance in Taiwan (TIST) study, initiated in 2006, is a nationwide surveillance program designed to longitudinally monitor thein vitroactivity of tigecycline against commonly encountered drug-resistant bacteria. This study compared thein vitroactivity of tigecycline against 3,014 isolates of clinically important drug-resistant bacteria using the standard broth microdilution and disk diffusion methods. Species studied included methicillin-resistantStaphylococcus aureus(MRSA;n= 759), vancomycin-resistantEnterococcus faecium(VRE;n= 191), extended-spectrum β-lactamase (ESBL)-producingEscherichia coli(n= 602), ESBL-producingKlebsiella pneumoniae(n= 736), andAcinetobacter baumannii(n= 726) that had been collected from patients treated between 2008 and 2010 at 20 hospitals in Taiwan. MICs and inhibition zone diameters were interpreted according to the currently recommended U.S. Food and Drug Administration (FDA) criteria and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The MIC90values of tigecycline against MRSA, VRE, ESBL-producingE. coli, ESBL-producingK. pneumoniae, andA. baumanniiwere 0.5, 0.125, 0.5, 2, and 8 μg/ml, respectively. The total error rates between the two methods using the FDA criteria were high: 38.4% for ESBL-producingK. pneumoniaeand 33.8% forA. baumannii. Using the EUCAST criteria, the total error rate was also high (54.6%) forA. baumanniiisolates. The total error rates between these two methods were <5% for MRSA, VRE, and ESBL-producingE. coli. For routine susceptibility testing of ESBL-producingK. pneumoniaeandA. baumanniiagainst tigecycline, the broth microdilution method should be used because of the poor correlation of results between these two methods.

scholarly journals Multidrug Resistant and Extensively Drug Resistant Bacteria: A Study

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Silpi Basak ◽  
Priyanka Singh ◽  
Monali Rajurkar
Keyword(s):  
Antimicrobial Resistance ◽  
Antibiotic Susceptibility ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Close Monitoring ◽  
Care Hospital ◽  
Drug Resistant ◽  
Bacterial Isolates ◽  
Bacterial Strains ◽  
Extensively Drug Resistant

Background and Objective. Antimicrobial resistance is now a major challenge to clinicians for treating patients. Hence, this short term study was undertaken to detect the incidence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacterial isolates in a tertiary care hospital.Material and Methods. The clinical samples were cultured and bacterial strains were identified in the department of microbiology. The antibiotic susceptibility profile of different bacterial isolates was studied to detect MDR, XDR, and PDR bacteria.Results. The antibiotic susceptibility profile of 1060 bacterial strains was studied. 393 (37.1%) bacterial strains were MDR, 146 (13.8%) strains were XDR, and no PDR was isolated. All (100%) Gram negative bacterial strains were sensitive to colistin whereas all (100%) Gram positive bacterial strains were sensitive to vancomycin.Conclusion. Close monitoring of MDR, XDR, or even PDR must be done by all clinical microbiology laboratories to implement effective measures to reduce the menace of antimicrobial resistance.

scholarly journals Physics Comes to the Aid of Medicine—Clinically-Relevant Microorganisms through the Eyes of Atomic Force Microscope

Pathogens ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 969
Author(s):  
Mateusz Cieśluk ◽  
Piotr Deptuła ◽  
Ewelina Piktel ◽  
Krzysztof Fiedoruk ◽  
Łukasz Suprewicz ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimicrobial Agents ◽  
Antimicrobial Treatment ◽  
Point Of View ◽  
Diagnostic Methods ◽  
Drug Resistant ◽  
Bacterial Strains ◽  
Force Microscopy ◽  
Atomic Force ◽  
Recent Developments

Despite the hope that was raised with the implementation of antibiotics to the treatment of infections in medical practice, the initial enthusiasm has substantially faded due to increasing drug resistance in pathogenic microorganisms. Therefore, there is a need for novel analytical and diagnostic methods in order to extend our knowledge regarding the mode of action of the conventional and novel antimicrobial agents from a perspective of single microbial cells as well as their communities growing in infected sites, i.e., biofilms. In recent years, atomic force microscopy (AFM) has been mostly used to study different aspects of the pathophysiology of noninfectious conditions with attempts to characterize morphological and rheological properties of tissues, individual mammalian cells as well as their organelles and extracellular matrix, and cells’ mechanical changes upon exposure to different stimuli. At the same time, an ever-growing number of studies have demonstrated AFM as a valuable approach in studying microorganisms in regard to changes in their morphology and nanomechanical properties, e.g., stiffness in response to antimicrobial treatment or interaction with a substrate as well as the mechanisms behind their virulence. This review summarizes recent developments and the authors’ point of view on AFM-based evaluation of microorganisms’ response to applied antimicrobial treatment within a group of selected bacteria, fungi, and viruses. The AFM potential in development of modern diagnostic and therapeutic methods for combating of infections caused by drug-resistant bacterial strains is also discussed.

An active domain HF-18 derived from hagfish intestinal peptide effectively inhibited drug-resistant bacteria in vitro/vivo

2020 ◽  
Vol 172 ◽  
pp. 113746
Author(s):  
Meiling Jiang ◽  
Xiaoqian Yang ◽  
Haomin Wu ◽  
Ya Huang ◽  
Jie Dou ◽  
...  
Keyword(s):  
Resistant Bacteria ◽  
Drug Resistant ◽  
Drug Resistant Bacteria

An unexpected discovery toward novel membrane active sulfonyl thiazoles as potential MRSA DNA intercalators

2020 ◽  
Vol 12 (19) ◽  
pp. 1709-1727 ◽  
Author(s):  
Yuan-Yuan Hu ◽  
Juan Wang ◽  
Tie-Jun Li ◽  
Rammohan R Yadav Bheemanaboina ◽  
Mohammad Fawad Ansari ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Inhibitory Concentration ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Dna Intercalators ◽  
Dna Targeting ◽  
Drug Resistant Bacteria

Aim: With the increasing emergence of drug-resistant bacteria, the need for new antimicrobial agents has become extremely urgent. This work was to develop sulfonyl thiazoles as potential antibacterial agents. Results & methodology: Novel hybrids of sulfonyl thiazoles were developed from commercial acetanilide and acetylthiazole. Hybrids 6e and 6f displayed excellent inhibitory efficacy against clinical methicillin-resistant Staphylococcus aureus (MRSA) (minimum inhibitory concentration = 1 μg/ml) without obvious toxicity toward normal mammalian cells (RAW 264.7). The combination uses were found to improve the antimicrobial ability. Further preliminary antibacterial mechanism experiments showed that the active molecule 6f could effectively interfere with MRSA membrane and insert into MRSA DNA. Conclusion: Compounds 6e and 6f could serve as potential DNA-targeting templates toward the development of promising antimicrobial agents.

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