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Antibiotics in the clinical pipeline at the end of 2015
There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.
Journal Article
Fix the antibiotics pipeline
Funding for biotech companies - venture capital or government grants - cannot cover this for a drug that will be sold mainly in short courses, and to which resistance may emerge. The bill would also enforce an expedited review of crucial new antibiotics by the US Food and Drug Administration (FDA) and encourages the FDA to designate life-saving antibiotics as a special regulatory class for priority review.
Journal Article
Antibiotics in the clinical pipeline in 2013
The continued emergence of multi-drug-resistant bacteria is a major public health concern. The identification and development of new antibiotics, especially those with new modes of action, is imperative to help treat these infections. This review lists the 22 new antibiotics launched since 2000 and details the two first-in-class antibiotics, fidaxomicin (
1
) and bedaquiline (
2
), launched in 2011 and 2012, respectively. The development status, mode of action, spectra of activity, historical discovery and origin of the drug pharmacophore (natural product, natural product derived, synthetic or protein/mammalian peptide) of the 49 compounds and 6 β-lactamase/β-lactam combinations in active clinical development are discussed, as well as compounds that have been discontinued from clinical development since 2011. New antibacterial pharmacophore templates are also reviewed and analyzed.
Journal Article
Global Fine Scale Changes in Ambient NO2 During COVID-19 Lockdowns
Nitrogen dioxide (NO2) is an important contributor to air pollution and can adversely
affect human health(1–9) . A decrease in NO2 concentrations has been reported as a result of lockdown measures to reduce the spread of COVID-19(10–20). Questions remain, however, regarding the relationship of satellite-derived atmospheric column NO2
data with health-relevant ambient ground-level concentrations, and the representativeness of limited ground-based monitoring data for global assessment.
Here we derive spatially resolved, global ground-level NO2 concentrations from NO2
column densities observed by the TROPOMI satellite instrument at sufficiently fine
resolution (approximately one kilometre) to allow assessment of individual cities
during COVID-19 lockdowns in 2020 compared to 2019. We apply these estimates to
quantify NO2 changes in more than 200 cities, including 65 cities without available
ground monitoring, largely in lower-income regions. Mean country-level
population-weighted NO2 concentrations are 29% ± 3% lower in countries with strict
lockdown conditions than in those without. Relative to long-term trends, NO2
decreases during COVID-19 lockdowns exceed recent Ozone Monitoring Instrument
(OMI)-derived year-to-year decreases from emission controls, comparable to 15 ± 4
years of reductions globally. Our case studies indicate that the sensitivity of NO2 to
lockdowns varies by country and emissions sector, demonstrating the critical need
for spatially resolved observational information provided by these satellite-derived
surface concentration estimates.
Journal Article
Emerging pathogenic links between microbiota and the gut–lung axis
Key Points
The gastrointestinal tract (GIT) and respiratory tract, although separate organs, are part of a shared mucosal immune system termed the gut–lung axis.
The microbiota of the GIT and the respiratory tract are involved in the gut–lung axis, influencing immune responses both locally and at distant sites.
Current research has identified specific bacterial taxa, their components and metabolites that can influence host immunity.
With greater knowledge of the gut–lung axis and microbial influences of immunity, advances have been made in understanding the role of the microbiota in respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD) and respiratory infection.
This newfound understanding has created several possible therapeutic strategies for the treatment or prevention of acute and chronic respiratory diseases. However, several technical challenges and unanswered questions remain.
The microbiota is central for host homeostasis and affects not only the gut but also other organs, including the lungs. In this Opinion article, Hansbro and colleagues explore the role of the microbiota in the gut–lung axis and lung disease.
The microbiota is vital for the development of the immune system and homeostasis. Changes in microbial composition and function, termed dysbiosis, in the respiratory tract and the gut have recently been linked to alterations in immune responses and to disease development in the lungs. In this Opinion article, we review the microbial species that are usually found in healthy gastrointestinal and respiratory tracts, their dysbiosis in disease and interactions with the gut–lung axis. Although the gut–lung axis is only beginning to be understood, emerging evidence indicates that there is potential for manipulation of the gut microbiota in the treatment of lung diseases.
Journal Article
Antibiotics in the clinical pipeline in 2011
The emergence of multi-drug-resistant bacteria and the lack of new antibiotics in the antibiotic drug development pipeline, especially those with new modes of action, is a major health concern. This review lists the 20 new antibiotics launched since 2000 and records the 40 compounds currently in active clinical development. Compounds in the pipeline from new antibiotic classes are reviewed in detail with reference to their development status, mode of action, spectrum of activity and lead discovery. In addition, the NP or synthetic derivation is discussed, with activity against Gram-negative bacteria highlighted.
Journal Article
A community-based approach to new antibiotic discovery
The Community for Open Antimicrobial Drug Discovery aims to tap into the potential of the millions of compounds distributed around laboratories globally to be a source of new antibiotic leads by offering free screening for antimicrobial properties, with no strings attached.
The Community for Open Antimicrobial Drug Discovery aims to tap into the potential of the millions of compounds distributed around laboratories globally to be a source of new antibiotic leads by offering free screening for antimicrobial properties, with no strings attached.
Journal Article
Pharmacologic Blockade of JAK1/JAK2 Reduces GvHD and Preserves the Graft-Versus-Leukemia Effect
We have recently reported that interferon gamma receptor deficient (IFNγR-/-) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft-versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNγR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNγR-/- T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo-HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases.
Journal Article
Mapping the effects of drought on child stunting
As climate change continues, it is expected to have increasingly adverse impacts on child nutrition outcomes, and these impacts will be moderated by a variety of governmental, economic, infrastructural, and environmental factors. To date, attempts to map the vulnerability of food systems to climate change and drought have focused on mapping these factors but have not incorporated observations of historic climate shocks and nutrition outcomes. We significantly improve on these approaches by using over 580,000 observations of children from 53 countries to examine how precipitation extremes since 1990 have affected nutrition outcomes. We show that precipitation extremes and drought in particular are associated with worse child nutrition. We further show that the effects of drought on child undernutrition are mitigated or amplified by a variety of factors that affect both the adaptive capacity and sensitivity of local food systems with respect to shocks. Finally, we estimate a model drawing on historical observations of drought, geographic conditions, and nutrition outcomes to make a global map of where child stunting would be expected to increase under drought based on current conditions. As climate change makes drought more commonplace and more severe, these results will aid policy-makers by highlighting which areas are most vulnerable as well as which factors contribute the most to creating resilient food systems.
Journal Article