AmpR of Stenotrophomonas maltophilia is involved in stenobactin synthesis and enhanced β-lactam resistance in an iron-depleted condition

Abstract

Abstract Background Iron is an essential nutrient for almost all aerobic organisms, including Stenotrophomonas maltophilia. Fur is the only known transcriptional regulator presumptively involved in iron homeostasis in S. maltophilia. AmpR, a LysR-type transcriptional regulator, is known to regulate β-lactamase expression and β-lactam resistance in S. maltophilia. Objectives To identify the novel regulator involved in controlling the viability of S. maltophilia in an iron-depleted condition and to elucidate the underlying regulatory mechanisms. Methods The potential regulator involved in iron homeostasis was identified by studying the cell viabilities of different regulator mutants in 2,2′-dipyridyl (DIP)-containing medium. Iron-chelating activity was investigated using the chrome azurol S (CAS) activity assay. An iron source utilization bioassay was carried out to examine utilization of different iron sources. Gene expression was determined by quantitative real-time PCR, and the Etest method was used to evaluate antibiotic susceptibility. Results Of the 14 tested mutants, the ampR mutant, KJΔAmpR, showed a growth compromise in DIP-containing medium. AmpR regulated stenobactin synthesis in an iron-depleted condition, but showed little involvement in the uptake and utilization of ferri-stenobactin and ferric citrate. AmpR was up-regulated by iron limitation and β-lactam challenge. S. maltophilia clinical isolates grown under conditions of iron depletion were generally more resistant to β-lactams compared with conditions of iron repletion. Conclusions AmpR is a dual transcriptional regulator in S. maltophilia, which regulates the β-lactam-induced β-lactamase expression and iron depletion-mediated stenobactin synthesis. AmpR is, therefore, a promising target for the development of inhibitors.