Helicobacter pylori
is the primary cause of 78% of gastric cancer cases, providing an opportunity to prevent cancer by controlling a single bacterial pathogen within the complex gastric microbiota. We developed highly selective antimicrobial agents against
H. pylori
by fusing an
H. pylori
-binding guide peptide (MM1) to broad-spectrum antimicrobial peptides. The common dairy probiotic
Lactococcus lactis
was then engineered to secrete these guided antimicrobial peptides (gAMPs). When co-cultured
in vitro
with
H. pylori
, the gAMP probiotics lost no toxicity compared to unguided AMP probiotics against the target,
H. pylori
, while losing >90% of their toxicity against two tested off-target bacteria. To test binding to
H. pylori
, the MM1 guide was fused to green fluorescent protein (GFP), resulting in enhanced binding compared to unguided GFP as measured by flow cytometry. In contrast, MM1-GFP showed no increased binding over GFP against five different off-target bacteria. These highly selective gAMP probiotics were then tested by oral gavage in mice infected with
H. pylori
. As a therapy, the probiotics outperformed antibiotic treatment, effectively eliminating
H. pylori
in just 5 days, and also protected mice from challenge infection as a prophylactic. As expected, the gAMP probiotics were as toxic against
H. pylori
as the unguided AMP probiotics. However, a strong rebound in gastric species diversity was found with both the selective gAMP probiotics and the non-selective AMP probiotics. Eliminating the extreme microbial dysbiosis caused by
H. pylori
appeared to be the major factor in diversity recovery.
IMPORTANCE
Alternatives to antibiotics in the control of
Helicobacter pylori
and the prevention of gastric cancer are needed. The high prevalence of
H. pylori
in the human population, the induction of microbial dysbiosis by antibiotics, and increasing antibiotic resistance call for a more sustainable approach. By selectively eliminating the pathogen and retaining the commensal community,
H. pylori
control may be achieved without adverse health outcomes. Antibiotics are typically used as a therapeutic post-infection, but a more targeted, less disruptive approach could be used as a long-term prophylactic against
H. pylori
or, by extension, against other gastrointestinal pathogens. Furthermore, the modular nature of the guided antimicrobial peptide (gAMP) technology allows for the substitution of different guides for different pathogens and the use of a cocktail of gAMPs to avoid the development of pathogen resistance.