The Post-Antibiotic Era
Every year that passes sees an increasing percentage of clinical samples found to be antibiotic resistant. This alarming trend has led many to forsee a “Post-Antibiotic Era” where bacterial infections could not be easily controlled. All the major classes of antibiotics had already been found by the end of the 1970s, and with the introduction of each new antibiotic, resistant bacterial strains have quickly appeared. In addition, antibiotics kill a wide variety of bacteria, leading to a flattening of the microbiome diversity in the gut of the patient after treatment. This can lead to infections by other pathogens as well as disabling the microbiome’s general health benefits to the body.
An antibiotic replacement? Antimicrobial Peptides (AMPs)
AMPs are naturally produced by a wide variety of organisms, including humans, to stop bacterial infection. Unlike antibiotics, bacteria have a hard time developing resistance to AMPs. Could these be a substitute for antibiotics? Three major factors keep AMPs off the shelves:
- AMPs kill a wide variety of off-target bacteria, not just the pathogen, just like antibiotics.
- AMPs are expensive to produce.
- The stomach naturally destroys peptides, so oral delivery is difficult.
Guide peptides solve the off-target problem
In the Kearney Lab, we find guide peptides that specifically bind the targeted pathogenic bacterium. We then fuse these to AMPs. These guided AMPs have greatly reduced toxicity against off-target bacteria such as the beneficial inhabitants of the stomach or gut. However, adding the guides does not reduce AMP toxicity against the target bacterium.
Probiotics solve the expense and delivery problems
Probiotic bacteria are inexpensive to produce and several probiotics naturally reside in the gastrointestinal tract. We have engineered the probiotic bacterium, Lactococcus lactis, to express guided AMPs in the stomach where the AMPs can directly attack stomach pathogens. L. lactis has been a major part of dairy product production throughout human history and is a resident of the human stomach. Engineered probiotics are currently available commercially for other applications (https://zbiotics.com).
Testing guided AMP probiotics in a mouse model: Stopping H. pylori infection
Helicobacter pylori is responsible for over 78% of the gastric cancer cases, with over 750,000 deaths due to gastric cancer worldwide every year. We infected mice with this bacterium and then treated the mice with a single dose of the guided AMP probiotic. Within 5 days, the bacterium was eliminated from the stomach without the disruption of the gastric microbiome caused by normal antibiotics. The probiotic also worked well as a prophylactic, preventing the establishment of new H. pylori infections in mice previously provided with the probiotic (Microbiology Spectrum, in press).