Med-Chemist : "Quintessential Medicinal Chemistry"
Wednesday, October 8, 2014
Researchers Discover How Bacteria Resist Antibiotics in Hospitals
Tiny circles of DNA called plasmids appear to be the culprit. They can easily enter bacteria and move from one bacteria to another, and some carry a gene that makes bacteria drug-resistant, a new study finds.
"The plasmids we are talking about carry an antibiotic-resistant gene to a class of antibiotic called carbapenems," said the study's co-author, Dr. Tara Palmore, an infection control specialist at the U.S. National Institutes of Health.
Carbapenems are antibiotics of last resort, and carbapenem-resistant Enterobacteriaceae (CRE) are bacterial pathogens that pose a "formidable" threat to hospitalized patients, according to the research.
The incidence of CRE has quadrupled in the last decade in the United States, according to background information in the report. CRE has been detected in nearly 4 percent of hospitals and about 18 percent of long-term acute care facilities. In addition, the researchers noted, CRE are resistant to most, if not all, antibiotics. Investigations have reported a death rate of 40 percent to 80 percent from infection.
Given ongoing concerns that even bacteria like Klebsiella and Enterobacter -- which are found in the environment and in healthy stomachs -- are becoming increasingly resistant to last-resort antibiotics, the researchers set out to find some answers. Their report, published Sept. 17 inScience Translational Medicine, showed that plasmid transfer in hospitals is likely contributing to the increase in antibiotic-resistant bacteria.
Tuesday, October 7, 2014
FDA Approves Triumeq for the Treatment of HIV-1 Infection
In continuation of my update on Triumeq
ViiV Healthcare announced today that the U.S. Food and Drug Administration (FDA) has approved Triumeq (abacavir 600mg, dolutegravir 50mg and lamivudine 300mg) tablets for the treatment of HIV-1 infection. Triumeq is ViiV Healthcare’s first dolutegravir-based fixed-dose combination, offering many people living with HIV the option of a single-pill regimen that combines the integrase strand transfer inhibitor (INSTI) dolutegravir, with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine.
FDA Approves Contrave (bupropion/naltrexone) for Weight Management
In continuation of my update on bupropion/naltrexone
The U.S. Food and Drug Administration today approved Contrave (naltrexone hydrochloride and bupropion hydrochloride extended-release tablets) as treatment option for chronic weight management in addition to a reduced-calorie diet and physical activity.
Monday, October 6, 2014
FDA Approves Otezla (apremilast) for Moderate to Severe Plaque Psoriasis
In continuation of my update on Apremilast (brand name Otezla) is an orally available small molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast specifically inhibits PDE4 and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. It has anti-inflammatory activity.
FDA Approves Spiriva Respimat (tiotropium) for the Maintenance Treatment of COPD
We know that, Tiotropium bromide, is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Tiotropium bromide capsules for inhalation are co-promoted by Boehringer-Ingelheimand Pfizer under the trade name Spiriva. It is also manufactured and marketed by Cipla under trade name Tiova.
Now Boehringer Ingelheim Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved Spiriva Respimat (tiotropium bromide) inhalation spray for the long-term, once-daily
Friday, October 3, 2014
FDA Approves Vitekta (elvitegravir) for HIV-1 Infection
We know that, Elvitegravir (EVG, formerly GS-9137) is a drug used for the treatment of HIV infection. It acts as an integrase inhibitor. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008.[2][3][4]The drug gained approval by U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild.
Thursday, October 2, 2014
Scripps Research Institute Chemists Modify Antibiotic to Vanquish Resistant Bacteria
Scientists at The Scripps Research Institute (TSRI) have devised a new antibiotic based on vancomycin that is powerfully effective against vancomycin-resistant strains of MRSA and other disease-causing bacteria.
The new vancomycin analog appears to have not one but two distinct mechanisms of anti-microbial action, against which bacteria probably cannot evolve resistance quickly.
“This is the prototype of analogues that once introduced will still be in clinical use a generation or maybe even two generations from now,” said Dale L. Boger, the Richard and Alice Cramer Professor of Chemistry at TSRI.
The report by Boger and members of his laboratory was published recently online ahead of print by the Journal of the American Chemical Society.
Increasing Reports of Resistance
Vancomycin entered clinical use in 1958, five years after its isolation from microbes in a soil sample gathered by an American missionary in Borneo. For nearly six decades it has been useful against a wide range of bacteria, and it remains a standard weapon against methicillin-resistant Staphylococcus aureus (MRSA), a major cause of hospital-acquired infections. A compound closely related to vancomycin also has been widely used to protect livestock.
Since the late 1980s, there have been increasing reports of vancomycin resistance in classes of bacteria that usually succumb to the antibiotic, including MRSA. Although vancomycin remains useful, scientists have been looking for new drugs to replace it in cases—often life-threatening—where it no longer can help patients.
The Boger laboratory has focused on inventing improved versions of vancomycin rather than entirely new compounds. “Vancomycin has lasted in clinical use for more than 50 years, in part because it isn’t very vulnerable to antibiotic resistance,” Boger said. “Our thought has been that if we find a vancomycin analog that addresses this current source of resistance we’ll get another 50 years of use out of it.”
Vancomycin works by binding to the building blocks of bacterial cell walls, in a way that prevents their proper assembly and leaves bacteria too leaky to live and replicate. The resistance comes from a single amino-acid alteration that some bacteria make to those building blocks, so that the antibiotic molecule can no longer get a firm grip. That drops vancomycin’s potency by a factor of about 1,000.
‘Incredibly Potent’
In 2012, Boger and his team reported making a vancomycin analog—informally termed vancomycin amidine—with a subtly altered binding pocket that fastens about equally well to the original and resistant sites on bacterial cell wall subunits. To get the precise structural modification they needed, they had to come up with a method for the “total synthesis” of this vancomycin-based compound—a controlled, step-by-step construction using organic chemistry reactions in the lab, rather than a natural enzyme-mediated production within cells.
“Years of work in this lab culminated in a total synthesis strategy that not only allowed us access to this target compound, but also gave us the ability to perform almost any other chemical modification of vancomycin that we wished,” said Akinori Okano, first author of the new report, who is an assistant professor of chemistry at TSRI.
Vancomycin amidine turned out to have acceptable level of activity against vancomycin-resistant and -sensitive bacteria, yet there was room for improvement. Thus in the new study, Okano, Boger and their colleagues used their vancomycin synthesis methods to add an additional feature to the molecule—a peripheral chlorobiphenyl (CBP), long known as a general booster of vancomycin’s potency.
“To our delight, the combination of these modifications led to an incredibly potent molecule, well beyond anything we had expected,” said Okano.
Wednesday, October 1, 2014
FDA Approves Tybost (cobicistat) for use in the treatment of HIV-1 Infection
We know that, Cobicistat (formerly GS-9350) is a licensed drug for use in the treatment of infection with the human immunodeficiency virus (HIV).
Like ritonavir (Norvir), cobicistat is of interest for its ability to inhibit liver enzymes that metabolize other medications used to treat HIV, notably elvitegravir, an HIV integrase inhibitor. By combining cobicistat with elvitegravir, higher concentrations of the latter are achieved in the body with lower dosing, theoretically enhancing elvitegravir's viral suppression while diminishing its adverse side-effects. In contrast with ritonavir, the only other booster approved for use as a part of HAART, cobicistat has no anti-HIV activity of its own..
Now U.S. Food and Drug Administration (FDA) has approved Tybost (cobicistat), a CYP3A inhibitor used in combination with atazanavir or darunavir for the treatment of human immunodeficiency virus type 1 (HIV-1) infection..
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