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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,” says 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 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 says. “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 coauthors 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 says. “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,” says 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.”
