Molecular War and Peace: the Concurrent Path to Antibiosis and Antibiotic Resistance

Fernando Baquero, Rafael Cantón, Cristina Herencias, João A. Gama, Teresa M Coque

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. Some of these molecular aggregates could result in conformations capable of disrupting the assembly or stability of rival structures, thereby acting as proto-antibiotics in a precellular scenario. Concurrently, some other molecular aggregates may deactivate such proto-antibiotics, acting as primitive mechanisms of resistance. However, both production and protection mechanisms tended to coalesce as proto-antibiotic production began to act on the producers' own multimolecular assemblies. During a prolonged time, the chemical Thioester World, RNA World, and the biological Proto-Cellular World coexisted, and proto-organelles started to be influenced and protected by proto-antibiotics and proto-resistances. Antibiotic production and resistance remained associated, even at the stage of antibiotic polyketides, emerging under a more oxygenated landscape, resulting in early biosynthetic pathways giving rise to contemporary ones, mainly in Actinomycetota. This scenario of integrated action and reaction provided an ecological equilibrium where antibiotics were not necessarily killer agents, but just 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.