Peng Hui, Shen Jiangchuan, Edmonds Katherine A, Luebke Justin L, Hickey Anne K, Palmer Lauren D, Chang Feng-Ming James, Bruce Kevin A, Kehl-Fie Thomas E, Skaar Eric P, Giedroc David P
Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
Graduate Program in Biochemistry, Indiana University, Bloomington, Indiana, USA.
mSphere. 2017 Jun 21;2(3). doi: 10.1128/mSphere.00082-17. eCollection 2017 May-Jun.
is a commensal human pathogen and a major cause of nosocomial infections. As gaseous signaling molecules, endogenous hydrogen sulfide (HS) and nitric oxide (NO·) protect from antibiotic stress synergistically, which we propose involves the intermediacy of nitroxyl (HNO). Here, we examine the effect of exogenous sulfide and HNO on the transcriptome and the formation of low-molecular-weight (LMW) thiol persulfides of bacillithiol, cysteine, and coenzyme A as representative of reactive sulfur species (RSS) in wild-type and Δ strains of . CstR is a per- and polysulfide sensor that controls the expression of a sulfide oxidation and detoxification system. As anticipated, exogenous sulfide induces the operon but also indirectly represses much of the CymR regulon which controls cysteine metabolism. A zinc limitation response is also observed, linking sulfide homeostasis to zinc bioavailability. Cellular RSS levels impact the expression of a number of virulence factors, including the exotoxins, particularly apparent in the Δ strain. HNO, like sulfide, induces the operon as well as other genes regulated by exogenous sulfide, a finding that is traced to a direct reaction of CstR with HNO and to an endogenous perturbation in cellular RSS, possibly originating from disassembly of Fe-S clusters. More broadly, HNO induces a transcriptomic response to Fe overload, Cu toxicity, and reactive oxygen species and reactive nitrogen species and shares similarity with the regulon. This work reveals an HS/NO· interplay in that impacts transition metal homeostasis and virulence gene expression. Hydrogen sulfide (HS) is a toxic molecule and a recently described gasotransmitter in vertebrates whose function in bacteria is not well understood. In this work, we describe the transcriptomic response of the major human pathogen to quantified changes in levels of cellular organic reactive sulfur species, which are effector molecules involved in HS signaling. We show that nitroxyl (HNO), a recently described signaling intermediate proposed to originate from the interplay of HS and nitric oxide, also induces changes in cellular sulfur speciation and transition metal homeostasis, thus linking sulfide homeostasis to an adaptive response to antimicrobial reactive nitrogen species.
是一种人体共生病原体，也是医院感染的主要原因。作为气态信号分子，内源性硫化氢（HS）和一氧化氮（NO·）协同保护细胞免受抗生素应激，我们推测这涉及硝酰基（HNO）的介导作用。在此，我们研究了外源性硫化物和HNO对野生型和Δ菌株转录组的影响，以及作为活性硫物种（RSS）代表的杆菌硫醇、半胱氨酸和辅酶A的低分子量（LMW）硫醇多硫化物的形成。CstR是一种过硫化物和多硫化物传感器，可控制硫化物氧化和解毒系统的表达。正如预期的那样，外源性硫化物诱导了操纵子，但也间接抑制了许多控制半胱氨酸代谢的CymR调控子。还观察到锌限制反应，将硫化物稳态与锌的生物利用度联系起来。细胞内RSS水平影响许多毒力因子的表达，包括外毒素，这在Δ菌株中尤为明显。HNO与硫化物一样，诱导操纵子以及其他受外源性硫化物调控的基因，这一发现可追溯到CstR与HNO的直接反应以及细胞内RSS的内源性扰动，可能源于铁硫簇解体。更广泛地说，HNO诱导对铁过载、铜毒性、活性氧和活性氮物种的转录组反应，并与调控子具有相似性。这项工作揭示了在中HS/NO·的相互作用，这种相互作用影响过渡金属稳态和毒力基因表达。硫化氢（HS）是一种有毒分子，也是最近在脊椎动物中描述的气体信号分子，其在细菌中的功能尚不清楚。在这项工作中，我们描述了主要人类病原体对细胞内有机活性硫物种水平定量变化的转录组反应，这些物种是参与HS信号传导的效应分子。我们表明，硝酰基（HNO）是最近描述的一种信号中间体，推测其源自HS和一氧化氮的相互作用，它也会诱导细胞硫形态和过渡金属稳态的变化，从而将硫化物稳态与对抗微生物活性氮物种的适应性反应联系起来。
