Researchers at the Johns Hopkins University School of Medicine
have identified a new chemical compound that could block the growth of
the tuberculosis bacteria.
Suspecting that a particular protein in tuberculosis was likely to
be vital to the bacteria’s survival, the scientists screened 175,000
small chemical compounds. This identified a potent class of
compounds that selectively slows down the protein’s activity and,
in a test tube, blocks TB growth, demonstrating that the protein is
indeed a vulnerable target. The research has been published in the
January 29 edition of Chemistry & Biology.
This class of chemical compounds attacks TB by inhibiting
methionine aminopeptidase (MetAP), an essential enzyme found in
organisms ranging from bacteria to humans, and that clearly has been
conserved throughout evolution because of its important task of
ensuring the proper manufacture of proteins.
“The MetAP inhibitors we discovered are hits, or leads in the
sense that they provide a framework — a starting point — for the
future development of an anti-TB drug,” says Jun O Liu PhD Professor
of Pharmacology and Molecular Sciences, Johns Hopkins University
School of Medicine.
The scientists cautioned that although the MetAP inhibitors
prevent TB growth in test tubes, they have a long way to go before
being declared safe and effective to treat TB patients.
To understand how the MetAP inhibitors work, Liu suggests
thinking of proteins as a strand of pearls folded in unique 3-D
shapes, with each bead representing a protein building block, or
amino acid. Invariably, the first bead, or amino acid, in every
string, whether human or bacterial protein, is a methionine. The
methionine ultimately needs to be removed in order for the protein
to mature and fold correctly. Its removal is the job of enzymes
called methionine aminopeptidases, or MetAPs.
“If you knock out this enzyme in TB bacteria, the bacteria will
not survive,” Liu says. “We expected that would happen, and
confirmed it by manipulating how much enzyme is expressed to see
what happens to the sensitivity of the bacteria when inhibitors are
What caught the team by surprise, however, was finding a potent
class of compounds (called 2,3-dichloro-1, 4-naphthoquinone) that
inhibits this enzyme. That discovery involved the use of
large-scale, high-throughput screening of 175,000 compounds and
measuring the potencies of a dozen related hits against the enzyme.
The final experiment by the team was to test the MetAP inhibitors
on TB bacteria in culture to see if it had any effect on bacteria
“Judging from potency, a MetAP inhibibitor alone probably won’t
wipe out TB,” Liu says. “TB is so hard to treat that the standard
therapy involves a cocktail of multiple drugs; no single compound is
powerful enough. Our hope is that someday an inhibitor of MetAP will
become a new component to enhance the existing therapy.”
Video: Professor Jun Liu describes the job
of the enzyme methionine aminopeptidase.