Archive for October, 2012

Dealing with Antibiotic Resistance Through Anti-Virulence Factors

October 2, 2012 1 comment

This morning, a paper was published in mBio titled Inhibition of LpxC Protects Mice from Resistant Acinetobacter baumannii by Modulating Inflammation and Enhancing Phagocytosis. This is AMAZING. So I decided to put it in layman terms so those unaware may become interested. It’s a bit long, but I promise an interesting read.

Most, if not all, antibiotics used to treat septicemia target essential bacterial proteins, leading to either bacterial cell death or stasis and the prevention of cell growth. This then leads to the rapid clearing of the infection, saving the patient. However, in the case of Acinetobacter baumannii and many other opportunistic infections such as Pseudomonas or Staph, drug resistance has quickly spread and the fear of totally drug resistant (TDR) pathogens has become a reality.

A. baumannii  is a beast. Several strains have become resistant to every antibiotic we have, including our last line of defense Colistin, or Polymyxin E. (Side note: the use of polymyxin was previously avoided except as a last resort due to its toxicity.) But the mechanism by which A. baumannii kills its victims is tricky. A. baumannii produces a lipopolysaccharide (LPS), specifically Lipid A , that is recognized by toll-like receptor 4 (TLR-4) on our immune cells. After the immune system sees the LPS, it begins to produce a storm of cytokines and interleukins, triggering a cascade of events that activate several other features of the adaptive and innate immune systems telling it that something has invaded. Basically, the recognition of LPS causes the immune system to kick into overdrive. The immune system’s overzealousness eventually causes hypothermia and a slurry of symptoms, leading to the death of the patient. Seems counterintuitive doesn’t it?

Normally, after the immune system sees LPS it recruits antibodies and macrophages to quarantine and kill the bacteria with the LPS. In the case of A. baumannii, the bacteria overproduce LPS, and actually shed it, leaving a trail of LPS wherever it goes. The immune system constantly runs into the LPS, believing it to be bacteria, causing a cytokine storm and hyperactive immunity. For this reason we call LPS an endotoxin because of its toxicity to humans and is considered a virulence factor because of its ability to cause disease.

What this paper first demonstrates is that in mice with a defective TLR-4, meaning they cannot recognize LPS, the mice no longer have disease and can survive for much longer when infected with A. baumannii. The paper only shows up to 28 days, but 100% of the TLR-4 knockout mice survived through the infection. Granted, these mice can no longer mount an immune response against the bacteria, but the disease has been cured!

Furthermore, the authors investigated the use of a drug, LpxC-1, that inhibits the synthesis of LPS in A. baumannii. In theory, this drug will block the shedding of LPS, and prevent the cascade of immune response, preventing the disease and eventual death. The first important piece of information is that this drug does not inhibit A. baumannii growth. The drug is not a classic antibiotic, and does not kill the bacteria nor slow their growth. The authors found that the drug was able to prevent death of the mice, even though these bacteria were still coursing through their veins. Even more profound, is that LpxC-1 actually promoted the phagocytosis of the cells by macrophages, leading to a lower bacterial density in the mice.

This paper has some absolutely amazing results, and some fantastic figures and images of the histopathology of A. baumannii in mice. This is very promising work that may lead to new classes of antibiotics that treat the actual cause of disease rather than directly targeting bacteria. The ability of bacteria to readily evolve mechanisms of drug resistance through selective pressures of classical antibiotics leads us to shy away from those traditional antibiotics.

The paper, linked above, is an incredible read and I would recommend it to anybody in the biomedical sciences, and perhaps even those outside of the sciences. The journal is open source, and although the figures are public I have not included them in hopes that you will read the paper to investigate it yourself.