scholarly journals Siderophore–Antibiotic Conjugate Design: New Drugs for Bad Bugs?

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3314 ◽  
Author(s):  
Negash ◽  
Norris ◽  
Hodgkinson
Keyword(s):  
Molecular Design ◽  
Modern Medicine ◽  
New Drugs ◽  
Phase Iii ◽  
Health Concern ◽  
Phase Iii Clinical Trials ◽  
Antibiotic Drug ◽  
New Antibiotics ◽  
General Guide ◽  
New Strategies

Antibiotic resistance is a global health concern and a current threat to modern medicine and society. New strategies for antibiotic drug design and delivery offer a glimmer of hope in a currently limited pipeline of new antibiotics. One strategy involves conjugating iron-chelating microbial siderophores to an antibiotic or antimicrobial agent to enhance uptake and antibacterial potency. Cefiderocol (S-649266) is a promising cephalosporin–catechol conjugate currently in phase III clinical trials that utilizes iron-mediated active transport and demonstrates enhanced potency against multi-drug resistant (MDR) Gram-negative pathogens. Such molecules demonstrate that siderophore–antibiotic conjugates could be important future medicines to add to our antibiotic arsenal. This review is written in the context of the chemical design of siderophore–antibiotic conjugates focusing on the differing siderophore, linker, and antibiotic components that make up conjugates. We selected chemically distinct siderophore–antibiotic conjugates as exemplary conjugates, rather than multiple analogues, to highlight findings to date. The review should offer a general guide to the uninitiated in the molecular design of siderophore–antibiotic conjugates.

Something old, something new: revisiting natural products in antibiotic drug discovery

2014 ◽  
Vol 60 (3) ◽  
pp. 147-154 ◽  
Author(s):  
Gerard D. Wright
Keyword(s):  
Natural Products ◽  
New Drugs ◽  
Clinical Use ◽  
Antibiotic Resistant ◽  
Antibiotic Drug ◽  
New Antibiotics ◽  
Bacteria And Fungi ◽  
Antibiotic Discovery ◽  
Novel Drug ◽  
New Strategies

Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an “apocalyptic” threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

Recent Developments in Treatments for Metastatic Castration-resistant Prostate Cancer—A Mechanistic Perspective

2012 ◽  
Vol 08 (02) ◽  
pp. 89
Author(s):  
Guru Sonpavde ◽  
E David Crawford ◽  
◽  
Keyword(s):  
Prostate Cancer ◽  
Abiraterone Acetate ◽  
Chemotherapeutic Agents ◽  
New Drugs ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Microtubule Inhibitor ◽  
Phase Iii Clinical Trials ◽  
Castration Resistant ◽  
Radium 223

Over the past decade, the treatment landscape in metastatic castration-resistant prostate cancer (CRPC) has markedly changed, with the introduction of three new chemotherapeutic agents. The mechanism of CRPC is not fully understood, but it may result from multiple pathways, including a loss or androgen receptor (AR) specificity and increased downstream signalling activity that provide multiple targets for therapeutic agents. For some years, docetaxel was the mainstay of treatment in CRPC, but recently, cabazitaxel (a microtubule inhibitor), sipuleucel-T (a cancer vaccine), and abiraterone acetate (a CYP17 inhibitor) were approved for CRPC treatment. In Phase III clinical trials, these agents have shown significant improvements in survival—over mitoxantrone (for cabazitaxel) and over placebo (for sipuleucel-T and abiraterone acetate)—and were well tolerated. There are also two treatments in late-stage development, MDV3100 (an oral AR antagonist) and radium-223 (an isotope that creates breaks in double-stranded DNA). These have also shown improvements in survival in Phase III trials; their regulatory approval is expected soon. The modes of actions of the existing and new drugs in CRPC are varied, but some are complementary and investigations of different combinations of these medications are much needed; they may enhance efficacy, further extend survival, and improve outcomes in this formerly untreatable disease.

scholarly journals Glyconanoparticles as tools to prevent antimicrobial resistance

2021 ◽  
Author(s):  
Laura Morelli ◽  
Laura Polito ◽  
Barbara Richichi ◽  
Federica Compostella
Keyword(s):  
Antimicrobial Resistance ◽  
Control Measures ◽  
New Drugs ◽  
Health Concern ◽  
Global Public Health ◽  
Infection Control Measures ◽  
Microbial Infections ◽  
New Antibiotics ◽  
Improved Sanitation ◽  
Alternative Delivery

AbstractThe increased phenomenon of antimicrobial resistance and the slow pace of development of new antibiotics are at the base of a global health concern regarding microbial infections. Antibiotic resistance kills an estimated 700,000 people each year worldwide, and this number is expected to increase dramatically if efforts are not made to develop new drugs or alternative containment strategies. Increased vaccination coverage, improved sanitation or sustained implementation of infection control measures are among the possible areas of action. Indeed, vaccination is one of the most effective tools of preventing infections. Starting from 1970s polysaccharide-based vaccines against Meningococcus, Pneumococcus and Haemophilus influenzae type b have been licensed, and provided effective protection for population. However, the development of safe and effective vaccines for infectious diseases with broad coverage remains a major challenge in global public health. In this scenario, nanosystems are receiving attention as alternative delivery systems to improve vaccine efficacy and immunogenicity. In this report, we provide an overview of current applications of glyconanomaterials as alternative platforms in the development of new vaccine candidates. In particular, we will focus on nanoparticle platforms, used to induce the activation of the immune system through the multivalent-displacement of saccharide antigens. Graphical abstract

Small molecules in the treatment of psoriatic arthritis

2018 ◽  
Author(s):  
George E. Fragoulis ◽  
Iain B. McInnes
Keyword(s):  
Psoriatic Arthritis ◽  
Small Molecules ◽  
Unmet Needs ◽  
Clinical Manifestations ◽  
Clinical Impact ◽  
New Drugs ◽  
Phase Iii ◽  
Future Studies ◽  
Phase Iii Clinical Trials ◽  
Therapeutic Algorithm

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, occurring in about one third of psoriasis patients, and exhibiting very varied clinical manifestations and comorbidities. Although the clinical outcome of the disease has been significantly improved recently, mainly due to utilization of novel agents targeting the IL-23/-17 axis, unmet needs still exist. Emerging insights into the disease’s pathogenesis led to development of new drugs acting against critical molecular targets and their efficacy in psoriasis and/or PsA has been tested in Phase III clinical trials. Some of these therapeutic regimens have been already approved; some look promising but others have been proven inefficacious. Future studies are expected to determine the place of these compounds within the therapeutic algorithm of PsA. In this chapter we describe the rationale and clinical impact of incorporating small molecules in PsA treatment, as well as specific molecules involved in pathogenesis that may serve as therapeutic targets.

scholarly journals Targeting of Regulators as a Promising Approach in the Search for Novel Antimicrobial Agents

2022 ◽  
Vol 10 (1) ◽  
pp. 185
Author(s):  
Davide Roncarati ◽  
Vincenzo Scarlato ◽  
Andrea Vannini
Keyword(s):  
Biological Activity ◽  
Antibiotic Treatment ◽  
Bacterial Infections ◽  
Scientific Community ◽  
Antimicrobial Agents ◽  
Modern Medicine ◽  
High Potential ◽  
New Drugs ◽  
New Antibiotics ◽  
New Compounds

Since the discovery of penicillin in the first half of the last century, antibiotics have become the pillars of modern medicine for fighting bacterial infections. However, pathogens resistant to antibiotic treatment have increased in recent decades, and efforts to discover new antibiotics have decreased. As a result, it is becoming increasingly difficult to treat bacterial infections successfully, and we look forward to more significant efforts from both governments and the scientific community to research new antibacterial drugs. This perspective article highlights the high potential of bacterial transcriptional and posttranscriptional regulators as targets for developing new drugs. We highlight some recent advances in the search for new compounds that inhibit their biological activity and, as such, appear very promising for treating bacterial infections.

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

2001 ◽  
Vol 120 (5) ◽  
pp. A284-A284
Author(s):  
B NAULT ◽  
S SUE ◽  
J HEGGLAND ◽  
S GOHARI ◽  
G LIGOZIO ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Irritable Bowel Syndrome ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Irritable Bowel ◽  
Rome I

Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials

2001 ◽  
Vol 28 (6) ◽  
pp. 620-625 ◽  
Author(s):  
Pierre Falardeau ◽  
Pierre Champagne ◽  
Patrick Poyet ◽  
Claude Hariton ◽  
[Eacute]ric Dupont
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Naturally Occurring ◽  
Antiangiogenic Drug

Permeability Through Bacterial Porins Dictates Whole Cell Compound Accumulation

2020 ◽  
Author(s):  
Silvia Acosta Gutiérrez ◽  
Igor Bodrenko ◽  
Matteo Ceccarelli
Keyword(s):  
Cell Envelope ◽  
Scoring Function ◽  
Modern Medicine ◽  
New Drugs ◽  
Prediction Ability ◽  
Whole Cell ◽  
Virtual Libraries ◽  
Major Bottleneck ◽  
Global Threat ◽  
Bacterial Porins

The lack of new drugs for Gram-negative pathogens is a global threat to modern medicine. The complexity of their cell envelope, with an additional outer membrane, hinders internal accumulation and thus, the access of molecules to targets. Our limited understanding of the molecular basis for compound influx and efflux from these pathogens is a major bottleneck for the discovery of effective antibacterial compounds. Here we analyse the correlation between the whole-cell compound accumulation of ~200 molecules and their predicted porin permeability coefficient (influx), using a recently developed scoring function. We found a strong linear relationship (75%) between the two, confirming porins key role in compound penetration. Further, the remarkable prediction ability of the scoring function demonstrates its potentiality to guide the optimization of hits to leads as well as the possibility of screening ultra-large virtual libraries. Eventually, the analysis of false positives, molecules with high-predicted influx but low accumulation, provides new hints on the molecular properties behind efflux.<br>

scholarly journals Animal and Human Vaccines against West Nile Virus

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1073
Author(s):  
Juan-Carlos Saiz
Keyword(s):  
Clinical Trials ◽  
West Nile Virus ◽  
Vaccine Development ◽  
Phase Iii ◽  
West Nile ◽  
Specific Therapy ◽  
Phase Iii Clinical Trials ◽  
Neuroinvasive Disease ◽  
The Us ◽  
The Status

West Nile virus (WNV) is a widely distributed enveloped flavivirus transmitted by mosquitoes, which main hosts are birds. The virus sporadically infects equids and humans with serious economic and health consequences, as infected individuals can develop a severe neuroinvasive disease that can even lead to death. Nowadays, no WNV-specific therapy is available and vaccines are only licensed for use in horses but not for humans. While several methodologies for WNV vaccine development have been successfully applied and have contributed to significantly reducing its incidence in horses in the US, none have progressed to phase III clinical trials in humans. This review addresses the status of WNV vaccines for horses, birds, and humans, summarizing and discussing the challenges they face for their clinical advance and their introduction to the market.

scholarly journals The role of future treatments in the management of neovascular age-related macular degeneration in Europe

2021 ◽  
pp. 112067212110183
Author(s):  
Laurent Kodjikian ◽  
Carl Joe Mehanna ◽  
Salomon-Yves Cohen ◽  
François Devin ◽  
Sam Razavi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Real World Data ◽  
Phase Iii Clinical Trials ◽  
Age Related ◽  
Injection Frequency ◽  
Endothelial Growth Factor

Anti-vascular endothelial growth factor (VEGF) agents have transformed the management of patients with neovascular age-related macular degeneration (nAMD) over the past two decades. However, as more long-term real-world data become available, it is clear that treatment outcomes are inferior to those reported in large, controlled clinical trials. This is largely driven by undertreatment, that is, not maintaining a consistent injection frequency to achieve sustained VEGF suppression, whether due to patient non-compliance, an important injection burden, or non/incomplete anatomical response. Newer therapeutic advances under evaluation hold promise in achieving more, for less. We review the latest drugs currently in or having successfully finished phase III clinical trials, and determine their potential place in the management of patients with nAMD in Europe.

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