Molecular war and peace: the concurrent path to antibiosis and antibiotic resistance

The possibility of the emergence of proto-antibiotic and proto-resistance molecules in the prebiotic world, as primary elements involved in "molecular wars," is examined in this conceptual review. Throughout the Earth's early history, prebiotic chemical processes produced molecules that associated both randomly and persistently. Over time, those configurations that achieved greater stability were favored, their longevity effectively serving as a mechanism for prebiotic selection. Available chemical molecules or physical surfaces could stabilize and prolong the duration of certain aggregates, creating competition among them. Hypothetically, some aggregates could yield conformations capable of disrupting the assembly or stability of rival structures, thereby acting as proto-antimolecules and later evolving into proto-antibiotics in a primitive cellular scenario. Concurrently, some other molecular aggregates may deactivate such proto-antimolecules and antibiotics, acting as primitive mechanisms of resistance. Probably, both production and protection mechanisms tended to coalesce in multimolecular assemblies, ensuring the non-self-destruction of producers. Over a prolonged period, the chemical Thioester World, RNA World, and the biological Proto-Cellular World coexisted, and proto-organelles began to be influenced and protected by proto-antibiotics and proto-resistances. Antibiotic production and resistance remained associated, even at the stage of antibiotic polyketides, which progressively emerged in a more oxygenated landscape, with early biosynthetic pathways giving rise to contemporary ones, mainly in Actinomycota. This simultaneous action-and-reaction scenario provided an ecological equilibrium in which antibiotic molecules were not necessarily killer agents but rather regulatory signals within the microbiosphere, ensuring healthy bacterial interactions. The massive anthropogenic antibiotic production altered such an equilibrium, favoring an unbalanced resistance reaction through the massive diffusion of antibiotic resistance genes, now decoupled from antibiotic production and spreading across the microbial world, mostly carried in mobile genetic elements.