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 LPS modification by 4-amino-4-deoxy-L-arabinose; (ii) EnvZ/OmpR regulates the expression of the autotransporter gene
3832
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
mlaF
D173A
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 a
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.
Inhibition of vital respiratory enzymes, such as NADH: ubiquinone oxidoreductase (complex I), type II NADH-quinone oxidoreductases (NDH-2), and malate: quinone oxidoreductase, in the inner membrane, is a secondary antibacterial mechanism of colistin (1–3). However, colistin resistance mechanisms associated with this secondary mode of action of colistin have rarely been reported. Herein, we confirmed that the hypothetical protein gene
1038
was associated with colistin resistance in
Aeromonas hydrophila
by reducing antibiotic function in the inner membrane, providing novel knowledge on the generation of colistin resistance.
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