From Genome to Drugs: New Approaches in Antimicrobial Discovery

Decades of successful use of antibiotics is currently challenged by the emergence of increasingly resistant bacterial strains. Novel drugs are urgently required but, in a scenario where private investment in the development of new antimicrobials is declining, efforts to combat drug-resistant infections become a worldwide public health problem. Reasons behind unsuccessful new antimicrobial development projects range from inadequate selection of the molecular targets to a lack of innovation. In this context, increasingly available omics data for multiple pathogens has created new drug discovery and development opportunities to fight infectious diseases. Identification of an appropriate molecular target is currently accepted as a critical step of the drug discovery process. Here, we review how diverse layers of multi-omics data in conjunction with structural/functional analysis and systems biology can be used to prioritize the best candidate proteins. Once the target is selected, virtual screening can be used as a robust methodology to explore molecular scaffolds that could act as inhibitors, guiding the development of new drug lead compounds. This review focuses on how the advent of omics and the development and application of bioinformatics strategies conduct a “big-data era” that improves target selection and lead compound identification in a cost-effective and shortened timeline.

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Mass Ligand-Binding Screening Strategies for Identification of Leads for New Drug Discovery

PsycEXTRA Dataset ◽

10.1037/e495942006-003 ◽

1993 ◽

Author(s):

Ronald M. Burch ◽

Keyword(s):

Drug Discovery ◽

Ligand Binding ◽

New Drug ◽

Screening Strategies

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Faculty Opinions recommendation of Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717960880.793463821 ◽

2012 ◽

Author(s):

Neil Ryder

Keyword(s):

High Throughput ◽

High Throughput Screen ◽

New Drug ◽

Drug Lead

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Recent Advances in Drug Repurposing for Parkinson’s Disease

Current Medicinal Chemistry ◽

10.2174/0929867325666180719144850 ◽

2019 ◽

Vol 26 (28) ◽

pp. 5340-5362 ◽

Cited By ~ 2

Author(s):

Xin Chen ◽

Giuseppe Gumina ◽

Kristopher G. Virga

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drug Discovery ◽

De Novo ◽

Drug Repositioning ◽

Drug Repurposing ◽

Cost Effective ◽

New Drugs ◽

Recent Advances ◽

Clinical Drugs

:As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

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Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666191010144111 ◽

2019 ◽

Vol 22 (8) ◽

pp. 509-520

Author(s):

Cauê B. Scarim ◽

Chung M. Chin

Keyword(s):

Drug Discovery ◽

Chagas Disease ◽

Drug Candidates ◽

Lead Compounds ◽

New Drug ◽

Compound Libraries ◽

Screening Assays ◽

Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

Biomolecules ◽

10.3390/biom11050767 ◽

2021 ◽

Vol 11 (5) ◽

pp. 767

Author(s):

Priscila Baltazar Gonçalves ◽

Ana Carolina Rennó Sodero ◽

Yraima Cordeiro

Keyword(s):

Drug Discovery ◽

Neurodegenerative Diseases ◽

Green Tea ◽

Protein Misfolding ◽

Financial Burden ◽

Scientific Evidence ◽

Symptomatic Relief ◽

Public Health Problem ◽

Bioactive Compound ◽

Common Cause

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer’s disease (AD), and α-synuclein, linked to Parkinson’s disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

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Anti-meningococcal B vaccination in Italian adolescents: a cost-effective health opportunity

European Journal of Public Health ◽

10.1093/eurpub/ckaa166.586 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

D Panatto ◽

P Landa ◽

D Amicizia ◽

P L Lai ◽

E Lecini ◽

...

Keyword(s):

Large Scale ◽

Public Health Problem ◽

Vaccination Strategy ◽

Cost Effective ◽

Dose Schedule ◽

Developed Countries ◽

Invasive Disease ◽

International Setting ◽

The Impact

Abstract Background Invasive disease due to Neisseria meningitidis (Nm) is a serious public health problem even in developed countries, owing to its high lethality rate (8-15%) and the invalidating sequelae suffered by many (up to 60%) survivors. As the microorganism is transmitted via the airborne route, the only available weapon in the fight against Nm invasive disease is vaccination. Our aim was to carry out an HTA to evaluate the costs and benefits of anti-meningococcal B (MenB) vaccination with Trumenba® in adolescents in Italy, while also considering the impact of this new vaccination strategy on organizational and ethics aspects. Methods A lifetime Markov model was developed. MenB vaccination with the two-dose schedule of Trumenba® in adolescents was compared with 'non-vaccination'. Two perspectives were considered: the National Health Service (NHS) and society. Three disease phases were defined: acute, post-acute and long-term. Epidemiological, economic and health utilities data were taken from Italian and international literature. The analysis was conducted by means of Microsoft Excel 2010®. Results Our study indicated that vaccinating adolescents (11th year of life) with Trumenba® was cost-effective with an ICER = € 7,912/QALY from the NHS perspective and € 7,758/QALY from the perspective of society. Vaccinating adolescents reduces the number of cases of disease due to meningococcus B in one of the periods of highest incidence of the disease, resulting in significant economic and health savings. Conclusions This is the first study to evaluate the overall impact of free MenB vaccination in adolescents both in Italy and in the international setting. Although cases of invasive disease due to meningococcus B are few, if the overall impact of the disease is adequately considered, it becomes clear that including anti-meningococcal B vaccination into the immunization program for adolescents is strongly recommended from the health and economic standpoints. Key messages Free, large-scale MenB vaccination is key to strengthening the global fight against invasive meningococcal disease. Anti-meningococcal B vaccination in adolescents is a cost-effective health opportunity.

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Culturable bacteria associated with Anopheles darlingi and their paratransgenesis potential

Malaria Journal ◽

10.1186/s12936-020-03574-1 ◽

2021 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Elerson Matos Rocha ◽

Osvaldo Marinotti ◽

Deidre Machado Serrão ◽

Laura Viana Correa ◽

Ricardo de Melo Katak ◽

...

Keyword(s):

Public Health Problem ◽

Major Public Health Problem ◽

Culturable Bacteria ◽

Anopheles Darlingi ◽

Next Generation ◽

Bacterial Strains ◽

Promising Alternative ◽

Breeding Sites ◽

Adult Females ◽

Microbiological Techniques

Abstract Background Malaria remains a major public health problem in South America, mostly in the Amazon region. Among newly proposed ways of controlling malaria transmission to humans, paratransgenesis is a promising alternative. Paratransgenesis aims to inhibit the development of parasites within the vector through the action of genetically modified bacteria. The first step towards successful paratransgenesis in the Amazon is the identification of Anopheles darlingi symbiotic bacteria, which are transmitted vertically among mosquitoes, and are not pathogenic to humans. Methods Culturable bacteria associated with An. darlingi and their breeding sites were isolated by conventional microbiological techniques. Isolated strains were transformed with a GFP expressing plasmid, pSPT-1-GFP, and reintroduced in mosquitoes by feeding. Their survival and persistence in the next generation was assessed by the isolation of fluorescent bacteria from eggs, larvae, pupae and adult homogenates. Results A total of 179 bacterial strains were isolated from samples from two locations, Coari and Manaus. The predominant genera identified in this study were Acinetobacter, Enterobacter, Klebsiella, Serratia, Bacillus, Elizabethkingia, Stenotrophomonas and Pantoea. Two isolated strains, Serratia-Adu40 and Pantoea-Ovo3, were successfully transformed with the pSPT-1-GFP plasmid and expressed GFP. The fluorescent bacteria fed to adult females were transferred to their eggs, which persisted in larvae and throughout metamorphosis, and were detected in adult mosquitoes of the next generation. Conclusion Serratia-Adu40 and Pantoea-Ovo3 are promising candidates for paratransgenesis in An. darlingi. Further research is needed to determine if these bacteria are vertically transferred in nature.

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