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Bacterial multidrug resistance problem solved by a broad-spectrum synthetic antibiotic

Posted in Advanced Drug Manufacturing Technology, Antibiotic resistance, Bacterial Resistance, Biochemical pathways, Cell Biology, Cell Biology, Signaling & Cell Circuits, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Carrier Design, Drug Delivery Platform Technology, Drug Development Process, Drug Discovery Chemistry, Drug Toxicity, Infectious Disease & New Antibiotic Targets, Microbiology, Molecular Genetics & Pharmaceutical, New Drug Approval, Pharmaceutical Drug Discovery, Population Health Management, Genetics & Pharmaceutical, Prescription Drugs Costs, Small Molecules in Development of Therapeutic Drugs, tagged Antibiotic resistance, antibiotics, antimicrobial resistance, bacteria, drug resistance, synthetic on March 1, 2023| Leave a Comment »

Bacterial multidrug resistance problem solved by a broad-spectrum synthetic antibiotic

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

There is an increasing demand for new antibiotics that effectively treat patients with refractory bacteremia, do not evoke bacterial resistance, and can be readily modified to address current and anticipated patient needs. Recently scientists described a promising compound of COE (conjugated oligo electrolytes) family, COE2-2hexyl, that exhibited broad-spectrum antibacterial activity. COE2-2hexyl effectively-treated mice infected with bacteria derived from sepsis patients with refractory bacteremia, including a CRE K. pneumoniae strain resistant to nearly all clinical antibiotics tested. Notably, this lead compound did not evoke drug resistance in several pathogens tested. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to abrogate bacterial cell viability and the evolution of drug-resistance. Impeding these bacterial properties may occur through alteration of vital protein–protein or protein-lipid membrane interfaces – a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis. The diversity and ease of COE design and chemical synthesis have the potential to establish a new standard for drug design and personalized antibiotic treatment.

Recent studies have shown that small molecules can preferentially target bacterial membranes due to significant differences in lipid composition, presence of a cell wall, and the absence of cholesterol. The inner membranes of Gram-negative bacteria are generally more negatively charged at their surface because they contain more anionic lipids such as cardiolipin and phosphatidylglycerol within their outer leaflet compared to mammalian membranes. In contrast, membranes of mammalian cells are largely composed of more-neutral phospholipids, sphingomyelins, as well as cholesterol, which affords membrane rigidity and ability to withstand mechanical stresses; and may stabilize the membrane against structural damage to membrane-disrupting agents such as COEs. Consistent with these studies, COE2-2hexyl was well tolerated in mice, suggesting that COEs are not intrinsically toxic in vivo, which is often a primary concern with membrane-targeting antibiotics. The COE refinement workflow potentially accelerates lead compound optimization by more rapid screening of novel compounds for the iterative directed-design process. It also reduces the time and cost of subsequent biophysical characterization, medicinal chemistry and bioassays, ultimately facilitating the discovery of novel compounds with improved pharmacological properties.

Additionally, COEs provide an approach to gain new insights into microbial physiology, including membrane structure/function and mechanism of drug action/resistance, while also generating a suite of tools that enable the modulation of bacterial and mammalian membranes for scientific or manufacturing uses. Notably, further COE safety and efficacy studies are required to be conducted on a larger scale to ensure adequate understanding of the clinical benefits and risks to assure clinical efficacy and toxicity before COEs can be added to the therapeutic armamentarium. Despite these limitations, the ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. It enables the construction of a spectrum of compounds with the potential for development as a new versatile therapy for the emergence and rapid global spread of pathogens that are resistant to all, or nearly all, existing antimicrobial medicines.

References:

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00026-9/fulltext#%20

https://pubmed.ncbi.nlm.nih.gov/36801104/

https://www.sciencedaily.com/releases/2023/02/230216161214.htm

https://www.nature.com/articles/s41586-021-04045-6

https://www.nature.com/articles/d43747-020-00804-y

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Nano-particles as Synthetic Platelets to Stop Internal Bleeding Resulting from Trauma

Posted in Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Frontiers in Cardiology and Cardiovascular Disorders, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Uncategorized, tagged Bleeding, injury, internal bleeding, nanoparticles, platelets, synthetic, trauma on August 22, 2012| 21 Comments »

Reported by: Dr. V. S. Karra, Ph.D.

“Emergency treatments for stopping the flow of blood from cuts and other external injuries save thousands of lives each year,” Lavik pointed out. “But we have nothing that emergency responders or military medics can use to stop internal bleeding permanently or at least long enough to get a patient to a hospital. There’s a tremendous need in the military, where almost 80 percent of battlefield traumas are blast injuries. In civilian life, there are many accidents, violence-related injuries and other incidents that result in internal bleeding.”

Lavik’s team, which is at Case Western Reserve University, was inspired by studies showing there are few options to treat soldiers in Afghanistan and Iraq who suffer internal injuries from the roadside bombs known as improvised explosive devices and other blasts. They wanted to develop a treatment military medics could use in the field to stabilize wounded soldiers en route to definitive care in a hospital.

“The military has been phenomenal at developing technology to halt bleeding, but the technology has been effective only on external or compressible injuries,” Lavik said. “An emergency treatment for internal bleeding could provide a broader ability to stop life-threatening hemorrhage.”

Currently, no effective treatments exist that are portable and can stop internal bleeding at the scene, Lavik explained. At the hospital, however, patients typically undergo surgery and receive donated platelets or something called factor VIIa, which helps with clotting, but both can cause immune problems. Factor VIIa also can potentially cause blood clots elsewhere in the body, not just at the site of bleeding, increasing stroke risk. Other alternatives have been developed in the laboratory, but they’ve had similar side effects and are not currently used in hospitals.

Lavik and colleagues are developing synthetic platelets. These are artificial versions of the disc-shaped particles in blood that collect on the jagged edges of cut blood vessels and launch the chain of biochemical events that result in formation of a clot that stops the flow of blood. The synthetic platelets are special nanoparticles, so small that 10 would fit across the width of a single human hair. Their role is to stick to natural platelets and leverage quicker and more efficient clotting at the site of an internal wound.

The nanoparticles are spheres that are made of the same polyester material used in dissolvable sutures, and they disappear from the body after doing their work. The particles have an outer coating of polyethylene glycol (PEG), the same thick, sticky substance used as a thickening agent in skin creams, toothpastes and other consumer products. Researchers then attach a peptide, or small piece of protein, that sticks to platelets. The end product is a white powder that has a shelf-life without refrigeration of at least two weeks — almost twice as long as the donated natural platelets now administered to control bleeding. Unlike donated platelets or factor VIIa, the synthetic platelets do not require refrigeration.

In tests on laboratory rats, stand-ins for humans in such experiments, the artificial platelets worked better than factor VIIa in stopping internal bleeding and increased survival, explained Lavik. Emergency medical technicians or battlefield medics could carry the powder out into the field to treat patients immediately, which could mean the difference between life and death, Lavik noted.

Lavik explained that the development process is ongoing, and it will take several years for the treatment to reach first-responders. So far, the nanoparticles appear safe, and all of the materials used to make them are already approved for medical use.

Erin Lavik, Sc.D., who described the advance toward developing synthetic platelets, said it is among the efforts underway world-wide to treat bleeding from “blunt-force” injuries ― in car accidents like the crash that killed Princess Diana, for instance, and the battlefield blast waves from bombs and other weapons that are the leading cause of battlefield deaths. Sports injuries, falls and other problems likewise can cause internal bleeding.

Progress toward a new emergency treatment for internal bleeding ― counterpart to the tourniquets, pressure bandages and Quick Clot products that keep people from bleeding to death from external wounds ― was reported at the 244^th National Meeting & Exposition of the American Chemical Society, the world’s largest scientific society.

source:

http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_ARTICLEMAIN&node_id=222&content_id=CNBP_030545&use_sec=true&sec_url_var=region1&__uuid=47976746-3740-4695-84cf-1c86fe3fbb81