October 11, 2012 — A new potential class of antibiotics
called LpxC inhibitors was recently found to block the ability of bacteria to
initiate the septic cascade, saving mice from lethal infection, although
agents did not kill the bacteria in vitro, as is the typical mechanism of
action of antibiotics.
Senior author, Brad Spellberg, MD, from the Los Angeles
Biomedical Research Institute at Harbor-UCLA Medical Center and the David
Geffen School of Medicine, Los Angeles, California, and colleagues report
their findings in an article published
online October 2 in mBio.
"Traditionally, people have tried to find antibiotics
that rapidly kill bacteria," noted Dr. Spellberg in an American Society
for Microbiology news release. "But we found a new class of antibiotics
which has no ability to kill Acinetobacter that can still protect, not by
killing the bug, but by completely preventing it from turning on host
inflammation."
Acinetobacter baumannii
is a Gram-negative bacillus (GNB) that is one of the most drug-resistant
pathogens in the United States and around the world. Strains of the bacterium
have become resistant to every US Food and Drug Administration–approved
antibiotic; thus, infections caused by this bacterium can be untreatable, and
as a result the risk for in-hospital mortality for A baumannii
infections is among the highest of all GNB.
The researchers first compared wild-type mice with
toll-like receptor 4 (TLR-4)-deficient mice and found that TLR-4 deficient
mice were highly resistant to lethal infection, whereas 100% of wild-type
mice died from infection. This indicated a role for TLR-4 and an inflammatory
immune response in the lethal effects of the bacteria. Surprisingly, despite the
fact that wild-type mice had 100% mortality and TLR4-deficient mice had no
mortality, there was no significant difference between the 2 groups in
bacteria burden. Thus, the lethality of infection was not related to how much
bacteria were present but, rather, to how much host inflammation occurred in
response to infection.
A baumannii
is also known to express lipopolysaccharide (LPS) on its surface, which binds
to TLR4 and thereby induces host production of inflammatory cytokines, such
as tumor necrosis factor and interleukin 6. According to the researchers,
more-virulent strains of A baumannii shed more LPS than less-virulent
strains, which prompted them to investigate whether LpxC-1, an inhibitor of
LpxC, an enzyme involved in LPS synthesis, could affect the pathogenicity of A
baumannii.
The researchers report that LpxC-1 treatment did not kill
the bacteria in vitro, but treatment with LpxC-1 did suppress LPS levels in A
baumannii in vitro and in vivo in mice during infection. As a result, the
treated infected mice also showed decreased markers of inflammation (P
< .01) and a higher survival rate (100% vs 0% compared with the placebo
group at 72 hours).
"Since there are few if any drugs in development with
the potential to treat lethal [drug-resistant] A baumannii infections,
the discovery that an entirely new class of compounds has therapeutic
potential is of great potential clinical importance," the authors write.
Block Organism's Lethal Action
"Unlike traditional antibiotics, LpxC-1 doesn't kill
the bacteria, it just shuts down the manufacture of the endotoxin and stops
the body from mounting the inflammatory immune response to it that is the
actual cause of death," Dr. Spellberg told Medscape Medical News.
He adds, "Resistance is caused by us trying to kill
bacteria, and bacteria not wanting to die." Traditional antibiotic
screens seek to find antibiotics that rapidly kill bacteria, which creates
selective pressure that drives antibiotic resistance. Finding antibiotics
that do not kill the bacteria but, rather, prevent them from causing illness
is a new and important direction to take to find treatments for highly
resistant infections and has the promise of driving resistance more slowly.
"There's a growing movement in infectious disease
therapy to control the host inflammation response in treatment rather than
just 'murdering' the organism," Liise-anne Pirofski, MD, from the Albert
Einstein College of Medicine in New York City, and a reviewer of the study
for mBio, stated in the news release. She adds, "This is a very elegant
and important validation that this approach can work — at least in
mice."
In an independent comment to Medscape Medical News,
Jian Li, PhD, from Monash University's Institute of Pharmaceutical Sciences
in Parkville, Victoria, Australia, stated that this study supports the idea
that even though the LPS inhibitor LpxC-1 itself does not kill bacterial
cells, treatment with LpxC-1 reduced immunopathogenesis, thereby enhancing bacterial
killing by the immune system.
"This approach is similar to antivirulence compounds
(eg, Quorum sensing inhibitors), which don't kill bacterial cells but make
bacterial cells less virulent. It is generally believed that such approaches
may not lead to development of resistance," Dr. Li told Medscape
Medical News.
According to Dr. Li, "clearly more preclinical and
clinical studies are required, and "it is important to examine if, like
traditional antibiotics, resistance to LPS inhibition would emerge after
suboptimal treatment with LPS inhibitors," he said.
"We believe it is important to combine
anti-immunopathogenic compounds (eg, LPS inhibitors) with traditional
antibiotics, an approach which would not only kill bacterial cells but also
make bacterial cells less virulent and pathogenic, thereby enhancing
clearance by the immune system."
Financial support was received from the National Institute
of Allergy and Infectious Diseases and from Pfizer. Several authors report
that they are employed by Pfizer and one author receives support from the
Canadian Institutes for Health Research. Dr. Li has disclosed no relevant
financial relationships.
mBio.
Published online October 2, 2012. Full text
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