Various Novel Colistin Resistance Mechanisms Interact To Facilitate Adaptation of Aeromonas hydrophila to Complex Colistin Environments

Aeromonas hydrophila, a heterotrophic and Gram-negative bacterium, has attracted considerable attention owing to the increasing prevalence of reported infections. Colistin is a last-resort antibiotic that can treat life-threatening infections caused by multidrug-resistant Gram-negative bacteria. However, the mechanisms underlying colistin resistance in A. hydrophila remain unclear. The present study reveals four novel colistin resistance mechanisms in A. hydrophila: (i) EnvZ/OmpR upregulates the expression of the arnBCADTEF operon to mediate lipopolysaccharide (LPS) modification by 4-amino-4-deoxy-L-arabinose, (ii) EnvZ/OmpR regulates the expression of the autotransporter gene3832 to decrease outer membrane permeability in response to colistin, (iii) deletion of envZ/ompR activates PhoP/PhoQ, which functions as a substitute two-component system to mediate the addition of phosphoethanolamine to lipid A via pmrC, and (iv) the mlaFD173A mutant confers high-level colistin resistance via upregulation of the Mla pathway. The EnvZ/OmpR two-component system-mediated resistance mechanism is the leading form of colistin resistance in A. hydrophila, which enables it to rapidly generate low- to medium-level colistin resistance. As colistin concentrations in the environment continue to rise, antibiotic resistance mediated by EnvZ/OmpR becomes insufficient to ensure bacterial survival. Consequently, A. hydrophila has developed an mlaF mutation that results in high-level colistin resistance. Our findings indicate that A. hydrophila can thrive in a complex environment through various colistin resistance mechanisms.

Automated summary

Aeromonas hydrophila has developed four novel colistin resistance mechanisms to adapt to the increasing antibiotic concentrations in the environment. Among them, the resistance mechanism mediated by the EnvZ/OmpR two-component system is the leading form that enables low- to medium-level colistin resistance.