Fig. 8: Schematic of the proposed evolutionary trajectory and adaptive advantages of resistance gene heterogeneity.
a A hypothetical evolutionary trajectory schematic illustrating blaCTX-M heterogeneity in the clinical ICU-3. A bacterium carrying a single blaCTX-M-65 represents the early stage, followed by the emergence of complex multicopy heterogeneity within a single clonal population. This includes duplication of blaCTX-M-65, with one copy acquiring either a single mutation (blaCTX-M-247/248) or two mutations (blaCTX-M-249). Under antibiotic pressure, transient tandem copies of the mutated gene may be generated. b Schematic of five models illustrating the adaptive advantages of multicopy heterogeneity of a β-lactamase gene on the same plasmid. The models include two non-heterogeneity and three heterogeneity scenarios, tested under hypothetical antibiotic A and B (such as the β-lactams) pressures. In non-heterogeneous models 1 and 2, bacteria are readily killed by either antibiotic. In heterogeneous models 3 and 4, at either the population or single-cell (multi-plasmid) level, plasmid loss during drug switching can still lead to elimination. Only in model 5, with plasmid-level multicopy heterogeneity, can bacteria maximize adaptability under both constant and switching drug pressures.
