Navigation Links
New compound defeats drug-resistant bacteria

PROVIDENCE, R.I. [Brown University] It's no wonder that medicine's effort to combat bacterial infections is often described as an arms race. When new drugs are developed to combat infections, the bacterial target invariably comes up with a deterrent.

A particularly ingenious weapon in the bacterial arsenal is the drug efflux pump. These pumps are proteins located in the membranes of bacteria that can recognize and expel drugs that have breached the membranes. In some cases, the bacterial pumps have become so advanced they can recognize and expel drugs with completely different structures and mechanisms.

"This turns out to be a real problem in clinical settings, especially when a bacterial pathogen acquires a gene encoding an efflux pump that acts on multiple antibiotics," said Jason Sello, assistant professor of chemistry at Brown University. "In the worst case scenario, a bacterium can go from being drug-susceptible to resistant to five or six different drugs by acquiring a single gene."

"That leaves two choices: Make more new and costly antibiotics or find a way around the pump. Sello and his group chose the latter. In a paper published in the journal Bioorganic and Medicinal Chemistry, the team reports it has discovered a new compound of C-capped dipeptides, called BU-005, to circumvent a family of drug-efflux pumps associated with Gram-positive bacteria, which include the dangerous MRSA and tuberculosis strains. Until that discovery, C-capped dipeptides were known to work only against an efflux pump family associated with Gram-negative bacteria.

"If drug efflux pumps are inhibited, then bacteria will be susceptible to drugs again," Sello said. "This approach is of interest because one would have to discover efflux pump inhibitors rather than entirely new kinds of antibacterial drugs."

Recently, a company called MPEX Pharmaceuticals discovered that specific C-capped dipeptides could block the efflux pumps of the RND family, which are responsible for much of the drug resistance in Gram-negative bacteria. One of these compounds developed at MPEX advanced to phase I of an FDA clinical trial. Sello and his co-authors investigated whether C-capped dipeptides could block the pumps of another drug efflux family, called the major facilitator superfamily (MFS), which is associated mostly with Gram-positive bacteria.

The Brown team thought that new and perhaps more potent C-capped dipeptide efflux pump blockers could be discovered. Since it is not possible to predict which C-capped dipeptides would be efflux pump blockers, they synthesized a collection of structurally diverse C-capped dipeptides and screened it for compounds with new or enhanced activities.

Normally, this is a four- to five-step process. Sello's group reduced that to two steps, taking advantage of a technique used in other chemistry practices, known as the Ugi reaction. Using this approach, the team was able to prepare dozens of different C-capped dipeptides. They assessed each compound's ability to block two efflux pumps in the bacterium Streptomyces coelicolor, a relative of the human pathogen Mycobacterium tuberculosis and which resists chloramphenicol, one of the oldest antibacterial drugs.

From a collection of nearly 100 C-capped dipeptides that they prepared and tested, the group discovered BU-005. The new compound excited the researchers because it prevented the MFS efflux pump family from expelling chloramphenicol. Until now, structurally related C-capped dipeptides had only been reported to prevent chloramphenicol expulsion by other drug efflux pump families.

"Our findings that C-capped dipeptides inhibit efflux pumps in both Gram-positive and Gram-negative bacteria should reinvigorate interest in these compounds," Sello said. "Moreover, our simplified synthetic route should make the medicinal chemistry on this class of compounds much simpler."

Two Brown undergraduate students, Daniel Greenwald '12, and Jessica Wroten '11, helped perform the research and are contributing authors on the paper.

Greenwald joined the team in his freshman year, after reaching out to Sello. "This project was the first real immersion I had into chemistry research at an advanced level," said Greenwald, of Madison, Wisc. "It was an amazing opportunity to be able to use the tools of synthetic chemistry to address problems from molecular biology. It was definitely one of the most engaging aspects of my experience at Brown."


Contact: Richard Lewis
Brown University

Related medicine news :

1. Compound shows promise against intractable heart failure
2. Sigma-Aldrich Reaches Agreement to Sell Pfizers Bioactive Small Molecule Compounds
3. Chemotherapy plus synthetic compound provides potent anti-tumor effect in pancreatic cancers
4. New pyrimidine compounds may lead to improved treatments for childhood brain cancer
5. Researchers find compound effective in destroying antibiotic-resistant biofilms
6. Compound enhances cancer-killing properties of agent in trials
7. Concentration, timing and interactions are key when it comes to dietary compounds
8. Breast cancer cells regulate multiple genes in response to estrogen-like compounds
9. Plant compound resveratrol shown to suppresses inflammation, free radicals in humans
10. Compounds in non-stick cookware may be associated with elevated cholesterol in children and teens
11. New investigational compound targets pancreatic cancer cells
Post Your Comments:
Related Image:
New compound defeats drug-resistant bacteria
(Date:11/30/2015)... ... November 30, 2015 , ... At Grand Dental PC, their priority ... , When you have dental problems, you need to turn to a dentist who ... and treat your needs, a friendly dentist who counsels you on the best ways ...
(Date:11/30/2015)... ... November 30, 2015 , ... Newly reviewed ... of Glen Ridge, NJ. He has both advanced training and considerable experience ... is also an expert in cosmetic dentistry. He is an active Spear ...
(Date:11/30/2015)... ... November 30, 2015 , ... ”Dying Words: The AIDS Reporting of Jeff Schmalz ... 2015, to coincide with World AIDS Day. The multi-media project will be in audio ... epidemic as he was dying of the disease. , A collaborative effort led by ...
(Date:11/30/2015)... ... 30, 2015 , ... Brenntag Specialties, Inc. (BSI) has been ... Nutraceutical Specialties products into oral solid dosage in the over the counter vitamin ... pleased to announce our expanded distribution agreement with ASI.” said Steve Brauer, President ...
(Date:11/30/2015)... PITTSBURGH, PA (PRWEB) , ... November 30, 2015 , ... ... quality of life in the womb. "My last baby had high blood pressure due ... way for mothers to protect their babies from noise pollution as well as radio ...
Breaking Medicine News(10 mins):
(Date:11/30/2015)... MOUNTAIN VIEW, Calif. , Nov. 30, ... has been the norm in U.S. medical ... obsolete. The increasingly popular accountable care payer-provider ... payment models and, in their wake, alter ... or quality-based payments will push forward new ...
(Date:11/30/2015)... LAKE, N.J. and SAN DIEGO ... and Arena Pharmaceuticals, Inc. (NASDAQ: ARNA ) today ... has accepted for filing the New Drug Application (NDA) ... the extended release formulation will offer patients a chronic ... ® ) is currently approved as an ...
(Date:11/30/2015)... MOUNTLAKE TERRACE, Wash. and ST. ... Cross and Express Scripts (NASDAQ: ESRX ) today ... benefit agreement. The partnership, which began in 1999, will ... --> --> After evaluating pharmacy ... process, Premera concluded that Express Scripts continues to offer ...
Breaking Medicine Technology: