Small RNA OxyS induces resistance to aminoglycosides during oxidative stress by controlling Fe–S cluster biogenesis in <i>Escherichia coli</i>

Fe-S clusters are essential cofactors involved in many reactions across all domains of life. Their biogenesis in <i>Escherichia coli</i> and other enterobacteria involves two machineries: Isc and Suf. Under conditions where cells operate with the Suf system, such as during oxidative stress or iron limitation, the entry of aminoglycosides is reduced, leading to resistance to these antibiotics. The transition between Isc and Suf machineries is controlled by the transcriptional regulator IscR. Here, we found that two small regulatory RNAs (sRNAs), FnrS and OxyS, control <i>iscR</i> expression by base pairing to the 5'-UTR of the <i>iscR</i> mRNA. These sRNAs act in opposite ways and in opposite conditions: FnrS, expressed in anaerobiosis, represses the expression of <i>iscR</i> while OxyS, expressed during oxidative stress, activates it. Using an <i>E. coli</i> strain experiencing protracted oxidative stress, we further demonstrate that <i>iscR</i> expression is rapidly and significantly enhanced in the presence of OxyS. Consequently, we further show that OxyS induces resistance to aminoglycosides during oxidative stress through regulation of Fe-S cluster biogenesis, revealing a major role for this sRNA.