Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


New compound defeats drug-resistant bacteria

Chemists at Brown University have synthesized a new compound that makes drug-resistant bacteria susceptible again to antibiotics.

The compound — BU-005 — blocks pumps that a bacterium employs to expel an antibacterial agent called chloramphenicol. The team used a new and highly efficient method for the synthesis of BU-005 and other C-capped dipeptides. Results appear in Bioorganic and Medicinal Chemistry.

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.”

A new way to attack drug-resistant bacteria: “If drug efflux pumps are inhibited, then bacteria will be susceptible to drugs again.”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.”

Babajide Okandeji, who earned his doctorate last May and is a new products quality control chemist at Waters Corp. in Taunton, Mass., is the paper’s first author.

Brown University funded the work. Greenwald was supported by a Royce Fellows Program. Wroten was funded by a Brown University Undergraduate Teaching and Research Assistantship (UTRA) during the summer of 2010.

Editors: Brown University has a fiber link television studio available for domestic and international live and taped interviews, and maintains an ISDN line for radio interviews. For more information, call (401) 863-2476.

Richard Lewis | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>