BUFFALO, N.Y. -- Biomedical scientists collaborating on
translational research at two Buffalo institutions are reporting
the discovery of a novel, and heretofore unrecognized, set of genes
essential for the growth of potentially lethal, drug-resistant
bacteria. The study not only reveals multiple, new drug targets for
this human infection, it also suggests that the typical methods of
studying bacteria in rich laboratory media may not be the best way
to identify much-needed antimicrobial drug targets.
The paper (http://mbio.asm.org/content/3/4/e00113-12)
focuses on a Gram-negative bacteria called A. baumanni. It is
published in the current issue of mBio, as an 'editor's choice'
paper. The findings may be relevant to other Gram-negative bacteria
A. baumannii is responsible for a growing number of
hospital-acquired infections around the world. It can be fatal to
patients with serious illnesses, the elderly and those who have had
surgeries. Infections also have been seen in soldiers returning
from Iraq and Afghanistan with battlefield injuries.
"Generally, healthy people don't get infected," explains lead
author Timothy C. Umland, PhD, research scientist at
Hauptman-Woodward Medical Research Institute (HWI) and professor of
structural biology in the University at Buffalo School of Medicine
and Biomedical Sciences. "But what's challenging about A. baumannii
is that it can survive in the hospital environment and is very hard
to eradicate with common disinfectants, leading to
Typically, the way that essential genes for microbial pathogens
are found is by growing the bacteria under optimal conditions, says
co-author Thomas A. Russo, MD, professor in the UB departments of
medicine and microbiology and immunology. Genes found to be
essential for growth are then entered into the Database of
Essential Genes (DEG), which contains genes considered essential
for the sustenance of each organism.
The researchers at HWI and UB decided to try to better
understand what A. baumannii needs in order to grow when infecting
"Laboratory conditions create a different type of environment
from what happens in patients," Umland says, "where certain
nutrients the bacteria need will be present in very low amounts and
where the bacteria encounter immune and inflammatory responses. We
were purposely trying to test for genes that are important for
growth in these more realistic environments."
The team performed a genetic screen designed to identify
bacterial genes absolutely required for the growth and survival of
A. baumannii in human ascites, a peritoneal fluid that accumulates
under a variety of pathologic conditions.
"We found that nearly all of these 18 genes had not been
identified as essential in the DEG because they weren't necessary
for growth in an ideal laboratory environment," explains Russo.
"This is a large set of genes that has been flying under the
He adds: "The biggest concern is that quite a few strains of A.
baumannii are resistant to nearly all anti-microbial drugs and some
strains are resistant to all of them. To make things worse, there
are no new agents being tested for human use in the drug pipeline
that are active against A. baumannii. This is a huge problem."
Not only do the new genes suggest brand new, high-value drug
targets for A. baumannii infections, but the genes that have been
identified may be relevant to other Gram-negative infections.
"So far, our computational models show that these genes seem to
be conserved across Gram-negative infections, meaning that they may
lead to new drugs that would be effective for other drug-resistant
infections as well," says Umland.
The researchers who collaborated on the study are now pursuing
antibacterial drug discovery efforts focused on the newly
identified bacterial targets.
The research was funded by grants from the Telemedicine and
Advance Technical Research Center of the U.S. Army Medical Research
and Materiel Command, an interdisciplinary grant from UB and a VA
Merit Review grant from the U.S. Department of Veterans
Other co-authors are: L. Wayne Schultz, PhD, of HWI and UB, and
Ulrike MacDonald, Janet M. Beanan and Ruth Olson of the UB
Department of Medicine, the Department of Microbiology and
Immunology and UB's Witebsky Center for Microbial Pathogenesis.