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Production of Norspermidine Contributes to Aminoglycoside Resistance in pmrAB Mutants of Pseudomonas aeruginosa
Ist Teil von
Antimicrobial agents and chemotherapy, 2019-10, Vol.63 (10)
Ort / Verlag
United States: American Society for Microbiology
Erscheinungsjahr
2019
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Emergence of resistance to polymyxins in
is mainly due to mutations in two-component systems that promote the addition of 4-amino-4-deoxy-l-arabinose to the lipopolysaccharide (LPS) through upregulation of operon
(
) expression. Here, we demonstrate that mutations occurring in different domains of histidine kinase PmrB or in response regulator PmrA result in coresistance to aminoglycosides and colistin. All seventeen clinical strains tested exhibiting such a cross-resistance phenotype were found to be
mutants. As shown by gene deletion experiments, the decreased susceptibility of the mutants to aminoglycosides was independent from operon
but required the efflux system MexXY-OprM and the products of three genes, PA4773-PA4774-PA4775, that are cotranscribed and activated with genes
Gene PA4773 (annotated as
in the PAO1 genome) and PA4774 (
) are predicted to encode enzymes involved in biosynthesis of polyamines. Comparative analysis of cell surface extracts of an
selected
mutant, called AB16.2, and derivatives lacking PA4773, PA4774, and PA4775 revealed that these genes were needed for norspermidine production via a pathway that likely uses 1,3-diaminopropane, a precursor of polyamines. Altogether, our results suggest that norspermidine decreases the self-promoted uptake pathway of aminoglycosides across the outer membrane and, thereby, potentiates the activity of efflux pump MexXY-OprM.