Novel Antibiotics That Don't Trigger Antibiotic Resistance Developed

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Novel Antibiotics That Don't Trigger Antibiotic Resistance Developed

Bacterial resistance to antibiotics is one of medicine's most vexing
challenges. In a study described in Nature Chemical Biology,
researchers from Albert Einstein College of Medicine of Yeshiva
University are developing a new generation of antibiotic compounds
that do not provoke bacterial resistance.

The compounds work against two notorious microbes: Vibrio cholerae,
which causes cholera; and E. coli 0157:H7, the food contaminant that
each year in the U.S. causes approximately 110,000 illnesses and 50
deaths.

Vern Schramm, Ph.D.Most antibiotics initially work extremely well,
killing more than 99.9% of microbes they target. But through mutation
and the selection pressure exerted by the antibiotic, a few bacterial
cells inevitably manage to survive, repopulate the bacterial
community, and flourish as antibiotic-resistant strains.

Vern L. Schramm, Ph.D., professor and Ruth Merns Chair of Biochemistry
at Einstein and senior author of the paper, hypothesized that
antibiotics that could reduce the infective functions of bacteria, but
not kill them, would minimize the risk that resistance would later
develop.

Dr. Schramm's collaborators at Industrial Research Ltd. earlier
reported transition state analogues of an enzyme that interferes with
"quorum sensing" — the process by which bacteria communicate with each
other by producing and detecting signaling molecules known as
autoinducers. These autoinducers coordinate bacterial gene expression
and regulate processes — including virulence — that benefit the
microbial community. Previous studies had shown that bacterial strains
defective in quorum sensing cause less-serious infections.

Rather than killing Vibrio cholerae and E. coli 0157:H7, the
researchers aimed to disrupt their ability to communicate via quorum
sensing. Their target: A bacterial enzyme, MTAN, that is directly
involved in synthesizing the autoinducers crucial to quorum sensing.
Their plan: Design a substrate to which MTAN would bind much more
tightly than to its natural substrate — so tightly, in fact, that the
substrate analog permanently "locks up" MTAN and inhibits it from
fueling quorum sensing.

To design such a compound, the Schramm lab first formed a picture of
an enzyme's transition state — the brief (one-tenth of one-trillionth
of a second) period in which a substrate is converted to a different
chemical at an enzyme's catalytic site. (Dr. Schramm has pioneered
efforts to synthesize transition state analogs that lock up enzymes of
interest. One of these compounds, Forodesine, blocks an enzyme that
triggers T-cell malignancies and is currently in a phase IIb pivitol
clinical study treating cutaneous T-cell leukemia.)

In the Nature Chemical Biology study, Dr. Schramm and his colleagues
tested three transition state analogs against the quorum sensing
pathway. All three compounds were highly potent in disrupting quorum
sensing in both V. cholerae and E. coli 0157:H7. To see whether the
microbes would develop resistance, the researchers tested the analogs
on 26 successive generations of both bacterial species. The 26th
generations were as sensitive to the antibiotics as the first.

"In our lab, we call these agents everlasting antibiotics," said Dr.
Schramm. He notes that many other aggressive bacterial pathogens — S.
pneumoniae, N. meningitides, Klebsiella pneumoniae, and Staphylococcus
aureus — express MTAN and therefore would probably also be susceptible
to these inhibitors.

While this study involves three compounds, Dr. Schramm says that his
team has now developed more than 20 potent MTAN inhibitors, all of
which are expected to be safe for human use: Since MTAN is a bacterial
enzyme, blocking it will have no effect on human metabolism.

Other Einstein researchers involved in the study were Jemy Gutierrez,
the lead author, Tamara Crowder, Agnes Rinaldo-Matthis, M. C. (Joseph)
Ho and Steven C. Almo. The powerful inhibitors were reported in an
earlier publication in collaboration with the Carbohydrate Chemistry
Team of Industrial Research Ltd., in New Zealand.

The compounds in this paper have been licensed to Pico
Pharmaceuticals, which plans to develop and initiate clinical trials
of transition-state analogues. Dr. Schramm is a Pico Pharmaceuticals
co-founder and chairman of its scientific advisory board.

http://www.sciencedaily.com/releases/2009/03/090313150121.htm

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