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Archive for the ‘Antibiotic resistance’ Category


The Journey of Antibiotic Discovery

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The term ‘antibiotic’ was introduced by Selman Waksman as any small molecule, produced by a microbe, with antagonistic properties on the growth of other microbes. An antibiotic interferes with bacterial survival via a specific mode of action but more importantly, at therapeutic concentrations, it is sufficiently potent to be effective against infection and simultaneously presents minimal toxicity. Infectious diseases have been a challenge throughout the ages. From 1347 to 1350, approximately one-third of Europe’s population perished to Bubonic plague. Advances in sanitary and hygienic conditions sufficed to control further plague outbreaks. However, these persisted as a recurrent public health issue. Likewise, infectious diseases in general remained the leading cause of death up to the early 1900s. The mortality rate shrunk after the commercialization of antibiotics, which given their impact on the fate of mankind, were regarded as a ‘medical miracle’. Moreover, the non-therapeutic application of antibiotics has also greatly affected humanity, for instance those used as livestock growth promoters to increase food production after World War II.

 

Currently, more than 2 million North Americans acquire infections associated with antibiotic resistance every year, resulting in 23,000 deaths. In Europe, nearly 700 thousand cases of antibiotic-resistant infections directly develop into over 33,000 deaths yearly, with an estimated cost over €1.5 billion. Despite a 36% increase in human use of antibiotics from 2000 to 2010, approximately 20% of deaths worldwide are related to infectious diseases today. Future perspectives are no brighter, for instance, a government commissioned study in the United Kingdom estimated 10 million deaths per year from antibiotic resistant infections by 2050.

 

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.

 

The increase in drug-resistant pathogens is a consequence of multiple factors, including but not limited to high rates of antimicrobial prescriptions, antibiotic mismanagement in the form of self-medication or interruption of therapy, and large-scale antibiotic use as growth promotors in livestock farming. For example, 60% of the antibiotics sold to the USA food industry are also used as therapeutics in humans. To further complicate matters, it is estimated that $200 million is required for a molecule to reach commercialization, with the risk of antimicrobial resistance rapidly developing, crippling its clinical application, or on the opposing end, a new antibiotic might be so effective it is only used as a last resort therapeutic, thus not widely commercialized.

 

Besides a more efficient management of antibiotic use, there is a pressing need for new platforms capable of consistently and efficiently delivering new lead substances, which should attend their precursors impressively low rates of success, in today’s increasing drug resistance scenario. Antibiotic Discovery Platforms are aiming to screen large libraries, for instance the reservoir of untapped natural products, which is likely the next antibiotic ‘gold mine’. There is a void between phenotanypic screening (high-throughput) and omics-centered assays (high-information), where some mechanistic and molecular information complements antimicrobial activity, without the laborious and extensive application of various omics assays. The increasing need for antibiotics drives the relentless and continuous research on the foreground of antibiotic discovery. This is likely to expand our knowledge on the biological events underlying infectious diseases and, hopefully, result in better therapeutics that can swing the war on infectious diseases back in our favor.

 

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.

 

References:

 

https://www.mdpi.com/2079-6382/8/2/45/htm

 

https://www.ncbi.nlm.nih.gov/pubmed/19515346

 

https://www.ajicjournal.org/article/S0196-6553(11)00184-2/fulltext

 

https://www.ncbi.nlm.nih.gov/pubmed/21700626

 

http://www.med.or.jp/english/journal/pdf/2009_02/103_108.pdf

 

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NEW Book #InfectiousDiseases #Immunology #StressSignaling #Therapeutics check https://www.amazon.com/dp/B075CXHY1B

Editor-in-Chief: Aviva Lev-Ari, PhD, RN

 

 

Includes FDA Approved Drugs for Infections and Infectious Diseases: Bacterial Infection, Viral Infection, Fungal Infection, Allergy-related Infections and Other, 1995 – 2016

VOLUME 2: covers the frontier of research on Infectious Diseases and the Human Immune System. The Immune Response, Disease Specific Immune Response, Immunodiagnostics and Immunotherapy, Immunotherapy and Autoimmunity,
Bacterial Infections, Bacteria Types, Antibactirial Therapeutics, FDA Approved Drugs for Infections and Infectious Diseases: Bacterial Infection, 1995 – 2016. Viral Infection: Virus Types, Antiviral Therapeutics, and FDA Approved Drugs for Infections and Infectious Diseases: Viral Infection, Fungal Infections, Allergy-related Infections, Other Infections,1995 – 2016,

VOLUME 3: covers the state of Science on the Historical Perspective of Immunology, Development of the Immune System, Signaling and Immunology, Cellular Immunity, Immunology and Inflammatory Response. Antibody-based Immunity, Vaccines and Microbiome, Immuno-Pharmaceutics, Cancer Immunotherapy, Immunomodulation and Neuro-Immunology.

Volume 2: Summary
The material that has been covered is a considerable material on the basic types of infections – bacterial, viral, and fungal, and diseases related to immune mechanisms. There has been a substantial coverage of the drugs and the manufacturers. This material brings to the discussion an international problem of drug resistance that applies much to bacteria, and a considerable amount of material on advances in drug development that takes into consideration protein structure and protein-protein interactions. The coverage of virus diseases brings to the forefront vaccines. However, in such cases as the influenza virus, a rapid genetic change of the virus makes the use of vaccines an issue for continuing revision.

Volume 3: Summary
The second volume is only concerned with the pathobiology of the inflammatory response, including sepsis, and it does not leave out hematopoiesis, and it lays out the difference between the B-clles and the T-cells that are related to the Toll receptor. Here we have looked closely at two immune disorders, Inflammatory Bowel Disease (Crohn’s Disease) and Rheumatoid Arthritis. Here we have discussed immunomodulation and signaling of the pathways involved, and the programmed cell death response. We have also covered the relationship of the immune response to autoimmune disorders and to cancer. The treatment of cancer now heavily leans toward the blocking of destructive processes in the immunomodulatory pathways.

Epilogue – Volume 2
Volume 2 has covered the most common bacterial and viral diseases that we find widely, or sporadically. It detailed the development of sepsis, and the immune response factor. The immune response involves local cellular invasion of lymphocytes related to initiation of T-cells and macrophages, and also the proteomic generated B-cell antibodies. These reactions are both local and systemic, as bacterial invasion is local and usually related to the tissue of residence (large intestine, oral, lung, genital). In the case of virus, the site of entry is often respiratory or by food intake, but these agents may rapidly become systemic. The other matter of the immune response is autoimmune, a reaction against the self. It is not entirely clear how this is initiated, but it has been related to failure to develop immunity in the prenatal or postnatal period. The only other possibility that might be considered would be by the mechanism of cell remodeling by an apoptotic related mechanism. The other chapters deal with therapeutics.

Epilogue – Volume 3
These two volumes have traversed a large knowledge-base. The first was directed largely at the well known bacterial, virus, fungal diseases, as well as autoimmunity. It specified recent FDA approved recommendations of pharmaceutics for these conditions. It also gives some attention to the immune response in inflammatory and autoimmune diseases, but not cancer. The second volume gives a concise history of development of Leukemias, Lymphomas pathology.

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Announcing our 10th e-Book on Amazon.com – 1st day, 9/4/2017

Editor-in-Chief: Aviva Lev-Ari, PhD, RN

 

On our Book Shelf on Amazon.com

WE ARE ON AMAZON.COM

https://www.amazon.com/s/ref=dp_byline_sr_ebooks_9?ie=UTF8&text=Aviva+Lev-Ari&search-alias=digital-text&field-author=Aviva+Lev-Ari&sort=relevancerank

http://www.amazon.com/dp/B00DINFFYC

http://www.amazon.com/dp/B018Q5MCN8

http://www.amazon.com/dp/B018PNHJ84

http://www.amazon.com/dp/B018DHBUO6

http://www.amazon.com/dp/B013RVYR2K

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http://www.amazon.com/dp/B019UM909A

http://www.amazon.com/dp/B019VH97LU

http://www.amazon.com/dp/B071VQ6YYK

https://www.amazon.com/dp/B075CXHY1B

 

The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The Immune System and Therapeutics (Series D: BioMedicine & Immunology) Kindle Edition – on Amazon.com since 9/4/2017

by Larry H. Bernstein (Author), Aviva Lev-Ari (Author), Stephen J. Williams (Author), Demet Sag (Author), Irina Robu (Author), Tilda Barliya (Author), David Orchard-Webb (Author), Alan F. Kaul (Author), Danut Dragoi (Author), Sudipta Saha (Editor)

https://www.amazon.com/dp/B075CXHY1B

 

Product details

  • File Size:21832 KB
  • Print Length:3747 pages
  • Publisher:Leaders in Pharmaceutical Business Intelligence (LPBI) Group; 1 edition (September 4, 2017)
  • Publication Date:September 4, 2017
  • Sold by:Amazon Digital Services LLC
  • Language:English
  • ASIN:B075CXHY1B
  • Text-to-Speech: Enabled 
  • X-Ray: Not Enabled 
  • Word Wise:Not Enabled
  • Lending:Enabled
  • Enhanced Typesetting:Not Enabled 

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Curator: Aviva Lev-Ari, PhD, RN

 

Transcriptomic Biomarkers to Discriminate Bacterial from Nonbacterial Infection in Adults Hospitalized with Respiratory Illness

Published online: 26 July 2017

URMC Researchers Developing New Tool to Fight Antibiotic Resistance

Goal is to Distinguish Between Viral and Bacterial Infections, Reduce Unnecessary Use of Antibiotics

Friday, July 28, 2017

“It’s extremely difficult to interpret what’s causing a respiratory tract infection, especially in very ill patients who come to the hospital with a high fever, cough, shortness of breath and other concerning symptoms,” said Ann R. Falsey, M.D., lead study author, professor and interim chief of the Infectious Diseases Division at UR Medicine’s Strong Memorial Hospital.

“My goal is to develop a tool that physicians can use to rule out a bacterial infection with enough certainty that they are comfortable, and their patients are comfortable, foregoing an antibiotic.”

Lead researcher Ann Falsey, M.D.

Ann R. Falsey, M.D.

Falsey’s project caught the attention of the federal government; she’s one of 10 semifinalists in the Antimicrobial Resistance Diagnostic Challenge, a competition sponsored by NIH and the Biomedical Advanced Research and Development Authority to help combat the development and spread of drug resistant bacteria. Selected from among 74 submissions, Falsey received $50,000 to continue her research and develop a prototype diagnostic test, such as a blood test, using the genetic markers her team identified.

SOURCE

https://www.urmc.rochester.edu/news/story/5108/urmc-researchers-developing-new-tool-to-fight-antibiotic-resistance.aspx

Lower respiratory tract infection (LRTI)

We enrolled 94 subjects who were microbiologically classified; 53 as “non-bacterial” and 41 as “bacterial”. RNAseq and qPCR confirmed significant differences in mean expression for 10 genes previously identified as discriminatory for bacterial LRTI. A novel dimension reduction strategy selected three pathways (lymphocyte, α-linoleic acid metabolism, IGF regulation) including eleven genes as optimal markers for discriminating bacterial infection (naïve AUC = 0.94; nested CV-AUC = 0.86). Using these genes, we constructed a classifier for bacterial LRTI with 90% (79% CV) sensitivity and 83% (76% CV) specificity. This novel, pathway-based gene set displays promise as a method to distinguish bacterial from nonbacterial LRTI.

https://www.nature.com/articles/s41598-017-06738-3#Sec8

IMAGE SOURCE

https://www.nature.com/articles/s41598-017-06738-3#Sec8

 

SOURCES

http://sciencemission.com/site/index.php?page=news&type=view&id=microbiology-virology%2Fnew-tool-to-distinguish&filter=8%2C9%2C10%2C11%2C12%2C13%2C14%2C16%2C17%2C18%2C19%2C20%2C27&redirected=1&redirected=1

https://www.urmc.rochester.edu/news/story/5108/urmc-researchers-developing-new-tool-to-fight-antibiotic-resistance.aspx

https://www.nature.com/articles/s41598-017-06738-3

Bacterial or Viral Infection? A New Study May Help Physicians …

 

Other related articles published in this Open Access Online Scientific Journal include the following:

Series D, VOLUME 2:

Infectious Diseases and Therapeutics

Author, Curator and Editor: Larry H Bernstein, MD, FCAP and CuratorSudipta Saha, PhD

 

Series D, VOLUME 3:

The Immune System and Therapeutics

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/biomed-e-books/series-d-e-books-on-biomedicine/human-immune-system-in-health-and-in-disease/

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