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 baumanniiinfections, 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
