scholarly journals Enhancers of host immune tolerance to bacterial infection discovered using linked computational and experimental approaches

2021 ◽  
Author(s):  
Megan M Sperry ◽  
Richard Novak ◽  
Vishal Keshari ◽  
Alexandre LM Dinis ◽  
Mark J Cartwright ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Metal Ion ◽  
Bacterial Infections ◽  
Transcriptional Profiling ◽  
Drug Repurposing ◽  
Xenopus Embryo ◽  
Infection Model ◽  
Embryo Survival ◽  
Pathogen Load ◽  
Host Tolerance

Current therapeutic strategies against bacterial infections focus on reduction of pathogen load through antibiotics; however, stimulation of host tolerance to infection might offer an alternative approach. Here we used computational transcriptomics and a Xenopus embryo infection model to rapidly discover infection response pathways, identify potential tolerance inducer drugs, and validate their ability to induce broad tolerance. Xenopus embryos exhibit natural tolerance to A. baumanii, K. pneumoniae, S. aureus, and S. pneumoniae bacteria, whereas A. hydrophila and P. aeruginosa produce infection that leads to death. Transcriptional profiling led to definition of a 20-gene signature that allows for discrimination between tolerant and susceptible states, as well as identification of active and passive tolerance responses based on the degree of engagement of gene transcription modulation. Upregulation of metal ion transport and hypoxia pathways reminiscent of responses observed in primate and mouse infection models were identified as tolerance mediators, and drug screening in the susceptible A. hydrophila infection model confirmed that a metal chelator (deferoxamine) and HIF-1α agonist (1,4-DPCA) increase embryo survival despite high pathogen load. These data demonstrate the value of combining the Xenopus embryo infection model with multi-omics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infection.

Procalcitonin Testingreduce Unnecessary Antibiotic Use in Bacterial Infection

2019 ◽  
Vol 2 (1) ◽  
pp. 1-3
Author(s):  
Attabak Toofani Milani ◽  
Mahshid Mohammadian ◽  
Sadegh Rostaminasab ◽  
Roghayeh Paribananaem ◽  
Zohre Ahmadi ◽  
...  
Keyword(s):  
Antibiotic Therapy ◽  
Bacterial Infection ◽  
Diagnostic Test ◽  
Bacterial Infections ◽  
Intervention Studies ◽  
Antibiotic Use ◽  
Clinical Suspicion ◽  
Diagnostic Biomarker ◽  
Clinical Routine ◽  
Initial Rise

Conventional diagnostic test have limitations to deferential diagnosis in clinical suspicion ofbacterial infection cases, that in some cases lead to inappropriate antibiotic therapy and increases antibiotic resistance. A new diagnostic insight is procalcitonin (PCT) test to improve diagnosis of bacterial infections and to guide antibiotic therapy. Serum PCT levels are of useful test as a biomarker in patients with bacterial infections for several reasons. Initial rise of PCT levels due to bacterial infection, subsequent sequential PCT levels can be used to assess the effectiveness and duration of antibiotic therapy. Based on clinical researches results, in bacterial infections, promising good results obtained when use of PCT used as differential diagnostic test. But further intervention studies are needed before use of PCT in clinical routine tests. The goal of this review is to study the PCT reliability as infections diagnostic biomarker.

Repurposing of auranofin against bacterial infections: An In silico and In vitro study

2020 ◽  
Vol 16 ◽  
Author(s):  
Nidhi Sharma ◽  
Arti Singh ◽  
Ruchika Sharma ◽  
Anoop Kumar
Keyword(s):  
Broad Spectrum ◽  
In Silico ◽  
Antibacterial Agent ◽  
Bacterial Infections ◽  
In Vitro Assays ◽  
Infection Model ◽  
Synergistic Activity ◽  
Bacterial Strains ◽  
Molecular Docking Study

Aim: The aim of the study was to find out the role of auranofin as a promising broad spectrum antibacterial agent. Methods: In-vitro assays (Percentage growth retardation, Bacterial growth kinetics, Biofilm formation assay) and In-silico study (Molegro virtual docker (MVD) version 6.0 and Molecular operating environment (MOE) version 2008.10 software). Results: The in vitro assays have shown that auranofin has good antibacterial activity against Gram positive and Gram negative bacterial strains. Further, auranofin has shown synergistic activity in combination with ampicillin against S. aureus and B. subtilis whereas in combination with neomycin has just shown additive effect against E. coli, P. aeruginosa and B. pumilus. In vivo results have revealed that auranofin alone and in combination with standard drugs significantly decreased the bioburden in zebrafish infection model as compared to control. The molecular docking study have shown good interaction of auranofin with penicillin binding protein (2Y2M), topoisomerase (3TTZ), UDP-3-O-[3- hydroxymyristoyl] N-acetylglucosaminedeacetylase (3UHM), cell adhesion protein (4QRK), β-lactamase (5CTN) and arylsulphatase (1HDH) enzyme as that of reference ligand which indicate multimodal mechanism of action of auranofin. Finally, MTT assay has shown non-cytotoxic effect of auranofin. Conclusion: In conclusion, auranofin in combination with existing antibiotics could be developed as a broad spectrum antibacterial agent; however, further studies are required to confirm its safety and efficacy. This study provides possibility of use of auranofin apart from its established therapeutic indication in combination with existing antibiotics to tackle the problem of resistance.

scholarly journals Phage Resistance Is Associated with Decreased Virulence in KPC-Producing Klebsiella pneumoniae of the Clonal Group 258 Clade II Lineage

2021 ◽  
Vol 9 (4) ◽  
pp. 762
Author(s):  
Lucia Henrici De Angelis ◽  
Noemi Poerio ◽  
Vincenzo Di Pilato ◽  
Federica De Santis ◽  
Alberto Antonelli ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Parental Strain ◽  
Bacterial Infections ◽  
Capsular Polysaccharide ◽  
Galleria Mellonella ◽  
Bacterial Pathogen ◽  
Phage Resistance ◽  
Infection Model ◽  
Lytic Phage ◽  
Susceptible Host

Phage therapy is now reconsidered with interest in the treatment of bacterial infections. A major piece of information for this application is the definition of the molecular targets exploited by phages to infect bacteria. Here, the genetic basis of resistance to the lytic phage φBO1E by its susceptible host Klebsiella pneumoniae KKBO-1 has been investigated. KKBO-1 phage-resistant mutants were obtained by infection at high multiplicity. One mutant, designated BO-FR-1, was selected for subsequent experiments, including virulence assessment in a Galleria mellonella infection model and characterization by whole-genome sequencing. Infection with BO-FR-1 was associated with a significantly lower mortality when compared to that of the parental strain. The BO-FR-1 genome differed from KKBO-1 by a single nonsense mutation into the wbaP gene, which encodes a glycosyltransferase involved in the first step of the biosynthesis of the capsular polysaccharide (CPS). Phage susceptibility was restored when BO-FR-1 was complemented with the constitutive wbaP gene. Our results demonstrated that φBO1E infects KKBO-1 targeting the bacterial CPS. Interestingly, BO-FR-1 was less virulent than the parental strain, suggesting that in the context of the interplay among phage, bacterial pathogen and host, the emergence of phage resistance may be beneficial for the host.

scholarly journals Mechanistic insights into synergy between nalidixic acid and tetracycline against clinical isolates of Acinetobacter baumannii and Escherichia coli

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Amit Gaurav ◽  
Varsha Gupta ◽  
Sandeep K. Shrivastava ◽  
Ranjana Pathania
Keyword(s):  
Escherichia Coli ◽  
Acinetobacter Baumannii ◽  
Nalidixic Acid ◽  
Bacterial Infections ◽  
Clinical Isolates ◽  
Hospital Environment ◽  
Infection Model ◽  
Drug Resistant ◽  
E Coli

AbstractThe increasing prevalence of antimicrobial resistance has become a global health problem. Acinetobacter baumannii is an important nosocomial pathogen due to its capacity to persist in the hospital environment. It has a high mortality rate and few treatment options. Antibiotic combinations can help to fight multi-drug resistant (MDR) bacterial infections, but they are rarely used in the clinics and mostly unexplored. The interaction between bacteriostatic and bactericidal antibiotics are mostly reported as antagonism based on the results obtained in the susceptible model laboratory strain Escherichia coli. However, in the present study, we report a synergistic interaction between nalidixic acid and tetracycline against clinical multi-drug resistant A. baumannii and E. coli. Here we provide mechanistic insight into this dichotomy. The synergistic combination was studied by checkerboard assay and time-kill curve analysis. We also elucidate the mechanism behind this synergy using several techniques such as fluorescence spectroscopy, flow cytometry, fluorescence microscopy, morphometric analysis, and real-time polymerase chain reaction. Nalidixic acid and tetracycline combination displayed synergy against most of the MDR clinical isolates of A. baumannii and E. coli but not against susceptible isolates. Finally, we demonstrate that this combination is also effective in vivo in an A. baumannii/Caenorhabditis elegans infection model (p < 0.001)

Crystalline ruthenium polypyridyl nanoparticles: a targeted treatment of bacterial infection with multifunctional antibacterial, adhesion and surface-anchoring photosensitizer properties

2021 ◽  
Author(s):  
Chenyang Yin ◽  
Zekun Wang ◽  
Xiaoyuan Ding ◽  
Xiaoqing Chen ◽  
Jingyuan Wang ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Antibacterial Therapy ◽  
Bacterial Infections ◽  
Targeted Treatment ◽  
Ruthenium Polypyridyl ◽  
Surface Anchoring ◽  
Antibacterial Materials

Photodynamic antibacterial therapy employs nanocomposites as an alternative to traditional antibiotics for the treatment of bacterial infections. However, many of these antibacterial materials are less effective towards bacteria than traditional...

Bacterial Infection and Splenic Reticuloendothelial Function in Children with Hemoglobin SC Disease

PEDIATRICS ◽  
1983 ◽  
Vol 72 (1) ◽  
pp. 93-98
Author(s):  
George R. Buchanan ◽  
Susan J. Smith ◽  
Christine A. Holtkamp ◽  
John P. Fuseler
Keyword(s):  
Bacterial Infection ◽  
Bacterial Infections ◽  
Infection Risk ◽  
Bacterial Disease ◽  
Normal Children ◽  
Splenic Function ◽  
Focus Of Infection ◽  
Serious Bacterial Infections ◽  
Primary Focus ◽  
Hemoglobin Sc Disease

Although the epidemiology and pathophysiology of serious bacterial infection in homozygous sickle cell anemia (SS disease) have become increasingly well understood, information about infection risk and splenic reticuloendothelial function in hemoglobin SC disease is quite limited. Therefore, the type and frequency of invasive bacterial disease were examined in 51 children with SC disease followed for 370 person-years and splenic function was assessed in 31 patients by quantitation of pitted erythrocytes. Seven serious bacterial infections occurred in four of the patients, five due to Streptococcus pneumoniae and two to Haemophilus influenzae. A primary focus of infection was present in all episodes, none of which proved fatal. Although 30 episodes of pneumonia or chest syndrome occurred in 20 of the patients, a bacterial etiology was proven in only three instances. Splenic function was usually impaired, with a mean pit count of 7.1% ± 8.2% (range 0% to 22.9%). This is significantly greater than normal, but less than pit counts in patients with SS disease or asplenic subjects. Children with SC disease may have a greater risk of bacterial infection than normal children, but their infection rate is not nearly as high as that in patients with SS disease.

Atypical Bacterial Infections Explained by a Concomitant Virus Infection

PEDIATRICS ◽  
1985 ◽  
Vol 76 (3) ◽  
pp. 411-414
Author(s):  
Ron Dagan ◽  
Caroline B. Hall ◽  
Marilyn A. Menegus
Keyword(s):  
Early Childhood ◽  
Virus Infection ◽  
Bacterial Infection ◽  
Clinical Manifestation ◽  
Bacterial Infections ◽  
Recent Progress ◽  
Clinical Presentation ◽  
Virus Detection ◽  
Dual Infection ◽  
Dual Infections

Because both viral and bacterial infections are common during early childhood, dual infections are not unexpected. However, the clinical manifestation of such combined infections may be, difficult to interpret, and they are often misdiagnosed as "atypical bacterial infection." Five patients with concomitant viral-bacterial infections are described. In all five cases, virus detection enabled the physicians to better understand an otherwise puzzling clinical presentation. In view of the recent progress in rapid viral diagnoses and the potential of antiviral drugs, the possibility of dual infection should be investigated more often.

scholarly journals Implementation of a Pragmatic Biomarker-Driven Algorithm to Guide Antibiotic Use in the Pediatric Intensive Care Unit: the Optimizing Antibiotic Strategies in Sepsis (OASIS) II Study

2018 ◽  
Vol 9 (1) ◽  
pp. 36-43 ◽  
Author(s):  
Kevin J Downes ◽  
Julie C Fitzgerald ◽  
Emily Schriver ◽  
Craig L K Boge ◽  
Michael E Russo ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Bacterial Infection ◽  
Pediatric Intensive Care Unit ◽  
Bacterial Infections ◽  
Pediatric Intensive Care ◽  
Antibiotic Use ◽  
Antibiotic Administration ◽  
Period 2 ◽  
Rate Ratios

Abstract Background Biomarkers can facilitate safe antibiotic discontinuation in critically ill patients without bacterial infection. Methods We tested the ability of a biomarker-based algorithm to reduce excess antibiotic administration in patients with systemic inflammatory response syndrome (SIRS) without bacterial infections (uninfected) in our pediatric intensive care unit (PICU). The algorithm suggested that PICU clinicians stop antibiotics if (1) C-reactive protein &lt;4 mg/dL and procalcitonin &lt;1 ng/mL at SIRS onset and (2) no evidence of bacterial infection by exam/testing by 48 hours. We evaluated excess broad-spectrum antibiotic use, defined as administration on days 3–9 after SIRS onset in uninfected children. Incidence rate ratios (IRRs) compared unadjusted excess length of therapy (LOT) in the 34 months before (Period 1) and 12 months after (Period 2) implementation of this algorithm, stratified by biomarker values. Segmented linear regression evaluated excess LOT among all uninfected episodes over time and between the periods. Results We identified 457 eligible SIRS episodes without bacterial infection, 333 in Period 1 and 124 in Period 2. When both biomarkers were below the algorithm’s cut-points (n = 48 Period 1, n = 31 Period 2), unadjusted excess LOT was lower in Period 2 (IRR, 0.53; 95% confidence interval, 0.30–0.93). Among all 457 uninfected episodes, there were no significant differences in LOT (coefficient 0.9, P = .99) between the periods on segmented regression. Conclusions Implementation of a biomarker-based algorithm did not decrease overall antibiotic exposure among all uninfected patients in our PICU, although exposures were reduced in the subset of SIRS episodes where biomarkers were low.

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.

Sign in / Sign up

Export Citation Format

Share Document