Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New compound defeats drug-resistant bacteria

29.11.2011
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:
http://www.brown.edu

More articles from Life Sciences:

nachricht Closing the carbon loop
08.12.2016 | University of Pittsburgh

nachricht Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

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

14.10.2016 | Event News

 
Latest News

Closing the carbon loop

08.12.2016 | Life Sciences

Applicability of dynamic facilitation theory to binary hard disk systems

08.12.2016 | Physics and Astronomy

Scientists track chemical and structural evolution of catalytic nanoparticles in 3-D

08.12.2016 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>