The Essence of Nature Can be the Simplest (2)–Self‐Inhibition Boundary: Keeping Away From Extracellular Fenton Reactions

The formation of boundaries, or inhibition zones, between neighboring colonies is a prevalent phenomenon in nature, occurring not only between different species but also within the same species or even within a single colony. The first work in this series presents extracellular Fenton chemistry as an alternative mechanism for cellular energy production. Specifically, polyketide synthase (PKS)-derived polycyclic aromatic metabolites initiate and amplify robust extracellular Fenton reactions, whereas non-ribosomal peptide synthase (NRPS)-derived siderophores or iron chelators recycle iron and protect the host from the potentially harmful effects of these reactions. Our findings further demonstrate that extracellular Fenton reactions are pivotal in the formation of boundaries, both within and between strains and species. PKS-derived aromatic metabolites promote the establishment of self-inhibition boundaries, while NRPS-derived siderophores primarily alleviate these boundaries. Notably, the development of these boundaries can be modulated by adjusting media components, such as proteins and starch, thereby influencing metabolic pathways. Consequently, experimental methodologies should be redesigned not merely to assess the antibiotic properties of compounds or metabolites, but to investigate their involvement in extracellular Fenton reactions and self-protection mechanisms, which are fundamental to understanding their natural biological roles.