Development of Engineered Probiotics to Deliver Narrow-Spectrum Siderophore Antimicrobial Peptides Against Drug-Resistant Enteric Bacteria
Microbial Ecology and Applied Microbiology
Final Report Abstract
Our research focused on fighting multidrug-resistant (MDR) enteric bacteria, particularly Enterobacteriaceae, using class IIb microcins. These bacteria-produced compounds have the potential to serve as effective antimicrobial agents against human pathogens. Our first goal was to identify new class IIb microcins and develop a library of antimicrobial peptides aimed at tackling MDR Enterobacteriaceae. We utilized bioinformatics tools to mine publicly available data bases and discovered twelve previously unknown class IIb microcins across seven different Enterobacteriaceae species, including some that are found in nature and those that affect plants. Among our findings were three new groups of class IIb microcins (MccW, MccX, and MccZ) along with eight new variants of known ones. Our experiments showed that these microcins can inhibit a variety of MDR bacteria, including well-known pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. This was significant because it demonstrated for the first time that class IIb microcins can effectively target bacteria outside of the Enterobacteriaceae family. Our research indicates that class IIb microcins are more common in microbial communities than previously thought, suggesting they could be developed into new treatments for drug-resistant infections. In our second aim, we examined how effectively we could eliminate carbapenem-resistant Klebsiella pneumoniae from the gut of infected mice. We focused on MccI47, a specific class IIb microcin that we characterized for the first time and tested its ability to clear this harmful bacterium from the gastrointestinal tract. Mice infected with K. pneumoniae were given either a live strain of E. coli Nissle 1917 that produces MccI47, or a control treatment. The results showed a significant reduction in K. pneumoniae levels in the treated mice over a week, particularly with the engineered probiotic. In summary, our research highlights the promise of class IIb microcins, in effectively reducing the burden of MDR Enterobacteriaceae in the gastrointestinal tract. This work sets the stage for developing engineered live biotherapeutic products aimed at selectively removing these resistant pathogens from the gut, offering a hopeful strategy in the ongoing fight against antimicrobial resistance. As our understanding of these microcins evolves, we anticipate they will play a crucial role in future therapeutic approaches.
Publications
-
Microcin MccI47 selectively inhibits enteric bacteria and reduces carbapenem-resistant Klebsiella pneumoniae colonization in vivo when administered via an engineered live biotherapeutic. Gut Microbes, 14(1).
Mortzfeld, Benedikt M.; Palmer, Jacob D.; Bhattarai, Shakti K.; Dupre, Haley L.; Mercado-Lubio, Regino; Silby, Mark W.; Bang, Corinna; McCormick, Beth A. & Bucci, Vanni
-
Novel class IIb microcins show activity against Gram-negative ESKAPE and plant pathogens. eLife, 13.
Mortzfeld, Benedikt M.; Bhattarai, Shakti K. & Bucci, Vanni
