An unprecedented small RNA-riboswitch interaction controls the expression of a bifunctional pump essential for Staphylococcus aureus infection

Maintaining manganese and iron homeostasis is critical for the human pathogen Staphylococcus aureus. To counteract metal-based host defense strategies, S. aureus uses a combination of metal-sensing transcription factors and regulatory RNAs to maintain metal homeostasis. Here, we uncovered an unprecedented interaction between a cis- and a trans-acting regulatory RNAs controlling a conditionally essential gene, mntY, encoding a Mn efflux pump. This conserved RNA-RNA interaction between a Fe-responsive sRNA and a Mn-sensing riboswitch allows the integration of Fe- and Mn-related stresses to fine-tune mntY expression. We demonstrated a dual role for MntY in metalation of Mn-dependent exoenzymes and Mn detoxification, which is critical for S. aureus adaptation to both low and high Mn environments. Deletion of the mntY gene is strongly pleomorphic, causing growth defects, altering virulence factor expression, immune evasion, and survival during infection. These findings point to MntY as a promising new therapeutic target to combat multidrug-resistant staphylococcal infections.

维持锰与铁的稳态对于人类病原体金黄色葡萄球菌（Staphylococcus aureus）至关重要。为了对抗基于金属的宿主防御策略，金黄色葡萄球菌通过联用金属感应转录因子与调控RNA来维持金属稳态。本研究首次揭示了调控编码锰外排泵的条件必需基因mntY的顺式与反式调控RNA之间存在前所未有的相互作用。这种存在于铁响应小RNA（small RNA, sRNA）与锰感应核糖开关之间的保守RNA-RNA相互作用，能够整合铁与锰相关的胁迫信号，从而精准微调mntY的表达。我们证实了MntY在锰依赖胞外酶的金属化过程与锰解毒中发挥双重作用，这对于金黄色葡萄球菌适应低、高锰环境均至关重要。mntY基因的缺失会引发强烈的多效性效应：导致生长缺陷、改变毒力因子表达、影响免疫逃逸以及感染过程中的存活能力。上述研究结果表明，MntY可作为对抗多药耐药葡萄球菌感染的极具潜力的新型治疗靶点。