May 21, 2002
Ramoplanin Beats Antibiotic Resistance
by Fighting the Battle on Its Own Terms
(Philadelphia,
PA) - In today's online early edition of the Proceedings
of the National Academy of Sciences, researchers
at the University of Pennsylvania School of Medicine
describe how one antibiotic currently under Phase III
clinical testing, ramoplanin, works on the molecular
level to disrupt the ability of bacteria to build cell
walls. The researchers believe that lessons learned
from ramoplanin may aid in developing new classes of
antibiotics for treatment of antimicrobial resistance.
"Ramoplanin is more effective than front line antibiotics
such as vancomycin. In comparison to vancomycin, ramoplanin's
relatively simplistic chemical architecture lends itself
well to chemical synthesis and modification - qualities
highly desirable for drug development," said Dewey
G. McCafferty, PhD, assistant professor in Penn's
Department of Biochemistry and Biophysics. "More
importantly, ramoplanin dodges the problems of antibiotic
resistance by attacking the bacteria in a spot that
cannot be easily overcome by normal mechanisms of mutational
resistance."
The ability of bacteria to acquire resistance to antibiotics
stands testament to the ingenuity of evolution and,
perhaps, to the overuse of bacteria-killing drugs. In
a sense, antibiotics replace natural selection in driving
changes in bacteria, as the survival of a single resistant
cell can lead to whole new population of resistant bacteria.
Distressingly, bacteria have grown resistant to vancomycin,
the antibiotic of last resort for more than 30 years.
Ramoplanin, however, has been found to be up to ten
times as powerful as vancomycin and no resistance to
the antibiotic has been reported to date.
Ramoplanin and vancomycin both attack the ability of
bacteria to cross link together cell wall building blocks
to form peptidoglycan, the large polymer made of sugars
and amino acids that provides mechanical strength for
the bacteria cell wall. Bacteria treated with ramoplanin
or vancomycin form weakened cell walls that spontaneously
burst, killing the cell. The difference is where the
two antibiotics make their attack on peptidoglycan biosynthesis.
"Vancomycin attaches to peptidoglycan monomers
at the end of the peptide chain, where two D-alanine
amino acid residues are found. The genes that cause
vancomycin resistance work by creating a competing peptidoglycan
monomer with a mutation that reduces the ability of
the antibiotic to bind. Vancomycin just bounces off
the cell surface and the bacteria goes unscathed,"
explained McCafferty. "Ramoplanin, however, attaches
itself to an essential sugar within the peptidoglycan
molecule. This interaction would be much more difficult
for evolutionary resistance mechanisms to overcome since
it would involve making multiple changes to the normal
way bacteria makes its cell wall."
Still, evolution has come up with clever solutions to
seemingly intractable problems in the past. That is
why McCafferty and his colleagues are exploring the
mechanism of action and chemical synthesis of ramoplanin.
Understanding how the antibiotic binds to peptidoglycan
would allow us to build even better antibiotics. As
it is, ramoplanin is substantially smaller and less
complicated than conventional antibiotics, which also
makes it easier to manufacture.
"Ramoplanin represents a genuinely new class of
antimicrobial for the treatment of drug-resistant bacterial
infections," said McCafferty. "Our discovery
of the molecular basis of its action will hopefully
lead to the development of smaller, simplistic drugs
derived from ramoplanin's structure with better antibiotic
activity or more favorable biological properties."
Funding for this research was provided by the National
Institutes of Health, the American Cancer Society, and
the McCabe fund.
# # #
Editor's Note:
Dr. McCafferty has no financial stake in Biosearch
Italia (the patent-holder of ramoplanin) or any of its
licensees.
The University of Pennsylvania Health System (UPHS)
is an international leader in biomedical research, medical
education and quality care. UPHS is distinguished not
only by its historical significance - first hospital
(1751), first medical school (1765), first university
teaching hospital (1874), and first fully integrated
academic health system (1993) - but also by its position
as a major player on the world stage of medicine in
the 21st century.
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