Microcin MccI47 selectively inhibits enteric bacteria and reduces carbapenem-resistant Klebsiella pneumoniae colonization in vivo when administered via an engineered live biotherapeutic

Intestinal colonization with multidrug-resistant Enterobacterales: screening, epidemiology, clinical impact, and strategies to decolonize carriers

“…More importantly, they engineered a Nissle 1917 Ec strain with a plasmid expressing MccI47. Then, the recombinant Ec was administered to mice, which showed the capacity to significantly reduce the amount of KPC- Kp colonizing the gut [ 249 ]. In another study, the ability of a bacteriophage cocktail and a genetically modified Ec strain Nissle 1917 producing Mcc-C7 (probiotic) to reduce gut colonization due to an ST131 Ec in a murine model was evaluated.…”

“…The in vivo mouse model has so far represented the gold-standard to study several aspects linked to the intestinal colonization due to Ent pathogens (e.g., [ 218 , 225 , 226 , 249 ]). Nevertheless, though this approach exhibits several advantages—such as the gastrointestinal similarities to humans—many strong limitations can be found in terms of cost, societal, ethical, and logistical issues, which can all together generate very long and laborious investigation periods [ 265 ].…”

Expanding the toolbox: Novel class IIb microcins show activity against gram-negative ESKAPE and plant pathogens

“…To test the newly identified microcins for antimicrobial activity in our previously established Ec overexpression system (13,16), all antimicrobial and immunity peptides were codon optimized, synthesized, and cloned into an inducible high copy vector (see Methods). Through static plate inhibition assays involving live-producing cells (13,16,26), we successfully validated the robust antimicrobial activity of eleven out of the twelve newly discovered microcins (Figure 2A). These microcins exhibit a range of specificities, with some inhibiting targets narrowly (e.g., Ps G492AI), while others exert a broader effect against multiple bacteria (e.g., Se G492AI).…”

“…The iron chelating moiety of these siderophore antimicrobial peptides (sAMPs) is recognized by high-affinity receptors and functions as a 'Trojan Horse' key to susceptible bacteria as it triggers import into the periplasmic space, where the peptide inhibits the molecular target of susceptible bacteria (19,(23)(24)(25). Because of these features, delivery of class IIb microcins by wildtype and engineered probiotics has been recently proposed as a strategy to combat drug-resistant enteric bacteria (12,13,16,26).…”

Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption

“…Although it is difficult to determine causality in an observational human study, especially with the temporal changes in antibiotic pressure that occur in this study, our data nevertheless imply that commensals have an intrinsic capacity to outcompete pathobionts and the ARGs they encode if they are able to evolve under the selective pressures of antibiotics. Microbiome therapeutics, including fecal transplant, rational microbial consortia, and engineered probiotics, are being pursued as a decolonization strategy for AMR-encoding pathobionts ( 93 – 95 ). Our data may suggest that antibiotic-tolerant commensal strains, possibly through resistance mutations, may paradoxically provide long-lasting suppression of AMR in the face of ongoing antibiotics and allow ongoing antibiotic therapy without the ordinarily deleterious effects on microbiome composition.…”