Nontyphoidal salmonellae (NTS) are exposed to reactive oxygen species (ROS) during their residency in the gut. To survive oxidative stress encountered during infection, salmonellae employ several mechanisms. One of these mechanisms involves the multidrug efflux pump MacAB, although the natural substrate of this pump has not been identified. MacAB homologs in pseudomonads secrete products of nonribosomal peptide synthesis (NRPS). In Salmonella enterica serovar Typhimurium, the siderophore enterobactin is produced by NRPS in response to iron starvation and this molecule can be processed into salmochelin and several linear metabolites. We found that Salmonella mutants lacking the key NRPS enzyme EntF are sensitive to peroxide mediated killing and cannot detoxify extracellular H₂O₂. Moreover, EntF and MacAB function in a common pathway to promote survival of Salmonella during oxidative stress. We further demonstrated that S. Typhimurium secretes siderophores in iron-rich media when peroxide is present and that these MacAB-secreted metabolites participate in protection of bacteria against H₂O₂. We showed that secretion of anti-H₂O₂ molecules is independent of the presence of the known siderophore efflux pumps EntS and IroC, well-described efflux systems involved in secretion of enterobactin and salmochelin. Both salmochelin and enterobactin are dispensable for S. Typhimurium protection against ROS; however, linear metabolites of enterobactin produced by esterases IroE and Fes are needed for bacterial survival in peroxide-containing media. We determined that linearized enterobactin trimer protects S. Typhimurium against peroxide-mediated killing in a MacAB-dependent fashion. Thus, we suggest that linearized enterobactin trimer is a natural substrate of MacAB and that its purpose is to detoxify extracellular reactive oxygen species.

中文翻译：

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通过MacAB外排泵分泌的线性化铁载体产品可保护肠炎沙门氏菌鼠伤寒沙门氏菌免受氧化应激。

非伤寒沙门氏菌（NTS）在肠道中驻留期间会暴露于活性氧（ROS）。为了抵抗感染期间遇到的氧化应激，沙门氏菌采用了几种机制。这些机制之一涉及多药外排泵MacAB，尽管尚未确定该泵的天然底物。假单胞菌中的MacAB同源物分泌非核糖体肽合成（NRPS）的产物。在肠炎沙门氏菌血清型鼠伤寒沙门氏菌中，铁磷肠杆菌素是由NRPS响应铁饥饿而产生的，该分子可以加工成沙门氏菌素和几种线性代谢物。我们发现缺少关键的NRPS酶EntF的沙门氏菌突变体对过氧化物介导的杀伤敏感，并且不能为细胞外H解毒₂ O ₂。此外，EntF和MacAB在共同途径中发挥作用，以提高氧化应激期间沙门氏菌的存活率。我们进一步证明S.鼠伤寒沙门氏菌中分泌富含铁的铁载体介质时过氧化物存在，并且这些MacAB分泌的代谢物参与针对H保护细菌的₂ ö ₂。我们表明，抗H ₂ O ₂分子的分泌与已知的铁载体外排泵EntS和IroC的存在无关，这是众所周知的肠内分泌细菌和沙门氏菌素分泌的外排系统。Salmochelin和Enterobactin都可用于S。鼠伤寒对ROS的保护；然而，由酯酶IroE和Fes产生的肠杆菌素的线性代谢产物是细菌在含过氧化物的培养基中存活所必需的。我们确定线性肠菌素三聚体保护S.鼠伤寒沙门氏菌对在MacAB依赖方式过氧化物介导的杀伤。因此，我们建议线性化的肠杆菌三聚体是MacAB的天然底物，其目的是对细胞外活性氧进行解毒。