New Type of Antibiotic May Be Less Prone to Resistance

Lara C. Pullen, PhD

January 08, 2015

Using a series of new techniques, researchers have isolated a novel antimicrobial compound called teixobactin, which may be just the first in a new class of antibiotics. Teixobactin is safe and effective in mice and does not appear to induce antimicrobial resistance.

Senior investigator Kim Lewis, PhD, from Northeastern University in Boston, Massachusetts, is hopeful teixobactin's efficacy will translate into a shorter course of treatment and a better adverse effect profile for patients.

"Mice are pretty good predictors of toxicity in people," he said at a press conference. "Another thing that sort of bodes well for this issue is that teixobactin kills exceptionally well...it has the ability to rapidly clear infections."

Losee L. Ling, PhD, from NovoBiotic Pharmaceuticals in Cambridge, Massachusetts, and colleagues published the result of their academia–industry collaboration online January 7 in Nature. In their article, they describe both their early efficacy data and their novel approach to the identification of teixobactin.

Teixobactin Is Safe and Effective

Teixobactin specifically binds to a highly conserved lipid that is a building block in the cell wall of gram-positive bacteria. It also simultaneously attacks additional critical bacterial targets.

The investigators have tested it in two mouse models of infection: blood infection with Staphylococcus aureus (animal model of methicillin-resistant S aureus) and lung infection with Streptococcus pneumoniae. All animals were successfully treated, and there were no adverse effects at the delivered dosages. Perhaps even more important, none of the mice developed resistance.

"It remains to be seen whether other mechanisms of resistance against teixobactin are out there in the environment, but the authors' findings suggest that a systematic search for Gram-negative bacteria producing antibiotics that target the Gram-positive cell wall could identify other 'resistance-light' antibiotics," writes Gerard Wright, PhD, from McMaster University in Hamilton, Ontario, Canada, in an accompanying editorial. "And reciprocal screens of Gram-positive producers for essential components of the Gram-negative outer membrane might identify similarly promising agents against pathogens of this bacterial class. Thus, in a field dominated by doom and gloom, Ling and colleagues' work offers hope that innovation and creativity can combine to solve the antibiotics crisis."

Bringing Teixobactin to Market

Efforts are underway to increase the solubility of teixobactin. "The compound has limited solubility...and that is, of course, something you want to improve.... You want to be able to deliver therapeutic doses," Dr Lewis explained.

The team expects to have the novel antibiotic in clinical trials in 2 years. Dr Lewis predicted that clinical trials will take an additional 2 to 3 years. If teixobactin makes it through clinical trials and is approved, it will be the first of a new class of antibiotics.

New Path of Discovery

"Pathogens are acquiring resistance faster than we can produce new antibiotics," Dr Lewis said at the press conference. This problem has been highlighted by the Centers for Disease Control and Prevention, the director of which has warned that we are fast approaching a "postantibiotic era."

Most of the currently available antibiotics have been isolated from microorganisms found in soil, and experts believe the soil has been thoroughly mined for antibiotics. Dr Ling and colleagues, however, have invented a new method to further explore the antimicrobial potential of bacteria in the soil.

The team realized that the bottleneck for isolating microorganisms from soil was the formation of the first colony in the agar. They thus developed a novel way to culture soil bacteria.

They created a "gadget" that contained agar that had been implanted with supernatant from a soil sample. The "contraption" acted as a diffusion chamber and was placed back into the soil, where it stayed for 1 to 2 weeks. "We are tricking the bacteria. They start growing and form colonies," explained Dr Lewis.

Their invention facilitated the formation of the critical first colony. Once the colony formed, the microorganism became "domesticated" and could be grown and screened in a traditional manner.

The team leveraged this concept to develop the iChip device, which Dr Lewis described as an advanced version of the diffusion chamber. It miniaturized the original design and allowed for faster and easier screening. Northeastern University owns the patent on this method, and NovoBiotic licensed the method to identify and grow the microorganisms from the soil.

The investigators used the iChip device to cultivate 10,000 soil bacteria. Many of the bacteria produced antibiotics.

Dr Lewis explained that the hit rate, or probability of finding antimicrobial activity from cell bacteria, is fairly high. Most of these compounds, however, have already been discovered, and thus are not interesting.

The investigators were able to identify 25 new antibiotics, the most promising of which is teixobactin. The organism that produces teixobactin produces it fairly well, and the investigators have not yet felt the need to optimize production.

Several of the authors are employees and consultants of NovoBiotic Pharmaceuticals. The other coauthors and Dr Wright have disclosed no relevant financial relationships.

Nature. Published online January 7, 2015. Full text

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