Given the increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for ...many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures-platforms-that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines. During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.
The low rate of discovery and rapid spread of resistant pathogens have made antibiotic discovery a worldwide priority. In cell-based screening, the mechanism of action (MOA) is identified after ...antimicrobial activity. This increases rediscovery, impairs low potency candidate detection, and does not guide lead optimization. In this study, high-throughput Fourier-transform infrared (FTIR) spectroscopy was used to discriminate the MOA of 14 antibiotics at pathway, class, and individual antibiotic level. For that, the optimal combinations and parametrizations of spectral preprocessing were selected with cross-validated partial least squares discriminant analysis, to which various machine learning algorithms were applied. This coherently resulted in very good accuracies, independently of the algorithms, and at all levels of MOA. Particularly, an ensemble of subspace discriminants predicted the known pathway (98.6%), antibiotic classes (100%), and individual antibiotics (97.8%) with exceptional accuracy, and similar results were obtained for simulated novel MOA. Even at very low concentrations (1 μg/mL) and growth inhibition (15%), over 70% pathway and class accuracy was achieved, suggesting FTIR spectroscopy can probe the grey chemical matter. Prediction of inhibitory effect was also examined, for which a squared exponential Gaussian process regression yielded a root mean square error of 0.33 and a
R
2
of 0.92, indicating that metabolic alterations leading to growth inhibition are intrinsically reflected on FTIR spectra beyond cell density.
Key points
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Antibiotic MOA and potency estimated with high-throughput FTIR spectroscopy
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Sub-inhibitory MOA identification suggests ability to explore grey chemical matter
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Data analysis optimization improved MOA identification at antibiotic level by 38%
The discovery of antibiotics has been slowing to a halt. Phenotypic screening is once again at the forefront of antibiotic discovery, yet Mechanism-Of-Action (MOA) identification is still a major ...bottleneck. As such, methods capable of MOA elucidation coupled with the high-throughput screening of whole cells are required now more than ever, for which Fourier-Transform Infrared (FTIR) spectroscopy is a promising metabolic fingerprinting technique. A high-throughput whole-cell FTIR spectroscopy-based bioassay was developed to reveal the metabolic fingerprint induced by 15 antibiotics on the
metabolism. Cells were briefly exposed to four times the minimum inhibitory concentration and spectra were quickly acquired in the high-throughput mode. After preprocessing optimization, a partial least squares discriminant analysis and principal component analysis were conducted. The metabolic fingerprints obtained with FTIR spectroscopy were sufficiently specific to allow a clear distinction between different antibiotics, across three independent cultures, with either analysis algorithm. These fingerprints were coherent with the known MOA of all the antibiotics tested, which include examples that target the protein, DNA, RNA, and cell wall biosynthesis. Because FTIR spectroscopy acquires a holistic fingerprint of the effect of antibiotics on the cellular metabolism, it holds great potential to be used for high-throughput screening in antibiotic discovery and possibly towards a better understanding of the MOA of current antibiotics.
Structural modifications of known antibiotic scaffolds have kept the upper hand on resistance, but we are on the verge of not having antibiotics for many common infections. Mechanism‐based discovery ...assays reveal novelty, exclude off‐target liabilities, and guide lead optimization. For that, we developed a fast and automatable protocol using high‐throughput Fourier‐transform infrared spectroscopy (FTIRS). Metabolic fingerprints of Staphylococcus aureus and Escherichia coli exposed to 35 compounds, dissolved in dimethyl sulfoxide (DMSO) or water, were acquired. Our data analysis pipeline identified biomarkers of off‐target effects, optimized spectral preprocessing, and identified the top‐performing machine learning algorithms for off‐target liabilities and mechanism of action (MOA) identification. Spectral bands with known biochemical associations more often yielded more significant biomarkers of off‐target liabilities when bacteria were exposed to compounds dissolved in water than DMSO. Highly discriminative models distinguished compounds with predominant off‐target effects from antibiotics with well‐defined MOA (AUROC > 0.87, AUPR > 0.79, F1 > 0.81), and from the latter predicted their MOA (AUROC > 0.88, AUPR > 0.70, F1 > 0.70). The compound solvent did not affect predictive models. FTIRS is fast, simple, inexpensive, automatable, and highly effective at predicting MOA and off‐target liabilities. As such, FTIRS mechanism‐based screening assays can be applied for hit discovery and to guide lead optimization during the early stages of antibiotic discovery.
Ribeiro da Cunha et al suggest mechanism‐based discovery assays to tap the grey chemical matter and reveal novelty, as well as for the exclusion of off‐target liabilities. The authors demonstrated that high‐throughput Fourier‐transform infrared spectroscopy (FTIRS) provides sufficiently sensitive metabolic fingerprints to predict predominant off‐target activity and to elucidate the mechanism of action of antibiotics, hence FTIRS can be applied for hit discovery and to guide lead optimization during the early stages of antibiotic discovery.
Current infection biomarkers are highly limited since they have low capability to predict infection in the presence of confounding processes such as in non-infectious inflammatory processes, low ...capability to predict disease outcomes and have limited applications to guide and evaluate therapeutic regimes. Therefore, it is critical to discover and develop new and effective clinical infection biomarkers, especially applicable in patients at risk of developing severe illness and critically ill patients. Ideal biomarkers would effectively help physicians with better patient management, leading to a decrease of severe outcomes, personalize therapies, minimize antibiotics overuse and hospitalization time, and significantly improve patient survival. Metabolomics, by providing a direct insight into the functional metabolic outcome of an organism, presents a highly appealing strategy to discover these biomarkers. The present work reviews the desired main characteristics of infection biomarkers, the main metabolomics strategies to discover these biomarkers and the next steps for developing the area towards effective clinical biomarkers.
There are two main strategies for antibiotic discovery: target-based and phenotypic screening. The latter has been much more successful in delivering first-in-class antibiotics, despite the major ...bottleneck of delayed Mechanism-of-Action (MOA) identification. Although finding new antimicrobial compounds is a very challenging task, identifying their MOA has proven equally challenging. MOA identification is important because it is a great facilitator of lead optimization and improves the chances of commercialization. Moreover, the ability to rapidly detect MOA could enable a shift from an activity-based discovery paradigm towards a mechanism-based approach. This would allow to probe the grey chemical matter, an underexplored source of structural novelty. In this study we review techniques with throughput suitable to screen large libraries and sufficient sensitivity to distinguish MOA. In particular, the techniques used in chemical genetics (e.g., based on overexpression and knockout/knockdown collections), promoter-reporter libraries, transcriptomics (e.g., using microarrays and RNA sequencing), proteomics (e.g., either gel-based or gel-free techniques), metabolomics (e.g., resourcing to nuclear magnetic resonance or mass spectrometry techniques), bacterial cytological profiling, and vibrational spectroscopy (e.g., Fourier-transform infrared or Raman scattering spectroscopy) were discussed. Ultimately, new and reinvigorated phenotypic assays bring renewed hope in the discovery of a new generation of antibiotics.
The low rate of discovery and rapid spread of resistant pathogens have made antibiotic discovery a worldwide priority. In cell-based screening, the mechanism of action (MOA) is identified after ...antimicrobial activity. This increases rediscovery, impairs low potency candidate detection, and does not guide lead optimization. In this study, high-throughput Fourier-transform infrared (FTIR) spectroscopy was used to discriminate the MOA of 14 antibiotics at pathway, class, and individual antibiotic level. For that, the optimal combinations and parametrizations of spectral preprocessing were selected with cross-validated partial least squares discriminant analysis, to which various machine learning algorithms were applied. This coherently resulted in very good accuracies, independently of the algorithms, and at all levels of MOA. Particularly, an ensemble of subspace discriminants predicted the known pathway (98.6%), antibiotic classes (100%), and individual antibiotics (97.8%) with exceptional accuracy, and similar results were obtained for simulated novel MOA. Even at very low concentrations (1 mug/mL) and growth inhibition (15%), over 70% pathway and class accuracy was achieved, suggesting FTIR spectroscopy can probe the grey chemical matter. Prediction of inhibitory effect was also examined, for which a squared exponential Gaussian process regression yielded a root mean square error of 0.33 and a R.sup.2 of 0.92, indicating that metabolic alterations leading to growth inhibition are intrinsically reflected on FTIR spectra beyond cell density.
RESUMO O tromboembolismo pulmonar é a complicação mais temida do tromboembolismo venoso (TEV) e a terceira causa de mortalidade cardiovascular no mundo, atrás apenas do infarto agudo do miocárdio e ...do acidente vascular cerebral. O risco de TEV é praticamente universal nos pacientes hospitalizados, especialmente naqueles com redução da mobilidade. Embora variável em incidência entre os pacientes clínicos e cirúrgicos, até 66,6% dos eventos relacionados às internações, podem ocorrer após a alta, permanecendo este risco por até 90 dias. Apesar de todo investimento feito na profilaxia do TEV nas últimas décadas, ainda não existem consensos ou diretrizes específicos para a sua prevenção em pacientes submetidos à cirurgia convencional de varizes dos membros inferiores. A adoção de um modelo de avaliação de risco validado para a profilaxia do TEV, embasado na literatura vigente, poderá ajudar na implementação e padronização da profilaxia do TEV na cirurgia convencional de varizes de membros inferiores, além deste benefício, poderá levar a diminuição do tempo de internação hospitalar e do número de reinternações.
ABSTRACT Pulmonary embolism is the most feared complication of venous thromboembolism (VTE) and the third leading cause of cardiovascular mortality in the world, after acute myocardial infarction and stroke. The risk of VTE is virtually universal in hospitalized patients, especially those with reduced mobility. Although variable in incidence between clinical and surgical patients, up to 66.6% of events related to hospitalizations can occur after discharge, with this risk remaining for up to 90 days. Despite all the investment made in VTE prophylaxis in recent decades, there is still no consensus or specific guidelines for its prevention in patients undergoing conventional surgery for varicose veins of lower limbs. The adoption of a validated risk assessment model for VTE prophylaxis, based on the current literature, may help in the implementation and standardization of VTE prophylaxis in conventional lower limb varicose vein surgery, in addition to this benefit, it may lead to a reduction in the length of hospital stay and the number of readmissions.
Ventriculo – Gallbladder shunt Porto Junior, Silvio; Ramos, João Victor Brito; da Cunha, Beatriz Lopes Bernardo ...
Journal of clinical neuroscience,
March 2024, 2024-Mar, 2024-03-00, 20240301, Letnik:
121
Journal Article
Recenzirano
•Ventriculo-gallbladder shunt offers a unique approach to treating hydrocephalus when other shunt options are not viable.•The gallbladder's ability to absorb and lyse proteins in cerebrospinal fluid ...makes it particularly effective in cases with high-protein CSF.•Literature indicates that it is a safe and efficient surgical technique, suitable for both adult and pediatric patients.•Complications such as gallstone formation and infections are reported but manageable, with no higher infection rate than other shunt types.•It has some specific characteristic techniques that must be know by the surgery team and shows promise for cases with excessive liquor production.
Abstract Introduction: Permanent liquor diversion is associated with a high risk of failure and often requires re-intervention. The ventriculo-gallbladder shunt (VGS) has been recognized as a last-resort alternative for treating hydrocephalus when the peritoneum or other distal sites are no longer suitable for receiving shunts. This article aims to report a case from a neurosurgery referral service in Brazil and review the literature on this issue. Methods: A systematic literature review was conducted in accordance with the PRISMA statement. The PubMed, Embase, and Web of Science databases were searched for data screening and extraction. The reported case was conducted with ethical approval from the neurosurgical hospital's ethics committee. Results: G.B.S, male, 43 years old, no comorbidities, who has been dealing with a 12-year history of hydrocephalus, with post-surgical chronic fungal meningitis. Two years ago, he underwent a ventriculoatrial shunt (VAS) placement due to multiple ventriculoperitoneal shunt (VPS) failures. Endocarditis was suspected, and the VAS was removed. As an alternative, VGS was implanted 6 months ago, and since then, there has been no need for a new system review. The gallbladder has an absorptive capacity of 1500 cc of liquid daily, which is more than the normal daily production of cerebrospinal fluid (CSF). Therefore, it is a good alternative when the ventriculoperitoneal shunt is not feasible due to postsurgical peritoneal adhesions or when there are contraindications for ventriculoatrial shunts. Conclusion: VGS is an alternative for patients who cannot undergo the most common surgical interventions, such as VPS. Keywords: Ventriculo-gallbladder; Shunt; Hydrocephalus; Ventriculo-vesicular; Gallbladder.
Circovirose suína França, Ticiana do Nascimento(Universidade Estácio de Sá Curso de Medicina Veterinária); Ribeiro, Carlos Torres; Cunha, Bernardo Melo da ...
Pesquisa Veterinária Brasileira,
06/2005, Letnik:
25, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Por meio de revisão da literatura pertinente foram coligidos e são apresentados os principais dados relativos aos aspectos epidemiológicos, clínicos, anátomo e histopatológicos observados na infecção ...por Circovírus Porcino tipo 2 (PCV-2) em suínos. São abordados a Síndrome Definhante Multissistêmica dos Suínos Desmamados (SDMDS), o Tremor Congênito Suíno (TCS), a Síndrome da Nefropatia e Dermatite Porcina (SNDP), bem como outras enfermidades associadas ou correlatas, a Síndrome Respiratória e Reprodutiva Porcina (SRRP), a Pneumonia Necrotizante Proliferativa (PNP) e as falhas reprodutivas. Uma vez que a SDMSD já foi registrada na Região Sul do Brasil e no Estado do Rio de Janeiro esse estudo objetiva chamar a atenção para o especial significado dessa virose para a suinocultura brasileira, em função dos prejuízos econômicos por ela determinados.
The literature of Porcine Circovirosis, including the main data on epidemiology and clinical, macroscopic and microscopic alterations of the infection of swine by Porcine Circovirus type 2 (PCV-2), is reviewed. There are various forms of infection: the Porcine Postweaning Multisystemic Wasting Syndrome (PMWS), Porcine Congenital Tremor, Porcine Dermatitis and Nephropathy Syndrome, and other associated or correlated diseases as the Porcine Reproductive and Respiratory Syndrome, Proliferative Necrotizing Pneumonia, and reproductive disorders. As PMWS already has been reported from southern Brazil and from the state of Rio de Janeiro, the objective of this review is to draw attention to the implications of this virosis for swine production in Brazil and its economical importance.
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