PmtA functions as a ferrous iron and cobalt efflux pump in <i>Streptococcus suis</i>

Transition metals are nutrients essential for life. However, an excess of metals can be toxic to cells, and host-imposed metal toxicity is an important mechanism for controlling bacterial infection. Accordingly, bacteria have evolved metal efflux systems to maintain metal homeostasis. Here, we established that PmtA functions as a ferrous iron [Fe(II)] and cobalt [Co(II)] efflux pump in <i>Streptococcus suis</i>, an emerging zoonotic pathogen responsible for severe infections in both humans and pigs. <i>pmtA</i> expression is induced by Fe(II), Co(II), and nickel [Ni(II)], whereas PmtA protects <i>S. suis</i> against Fe(II) and ferric iron [Fe(III)]-induced bactericidal effect, as well as Co(II) and zinc [Zn(II)]-induced bacteriostatic effect. In the presence of elevated concentrations of Fe(II) and Co(II), Δ<i>pmtA</i> accumulates high levels of intracellular iron and cobalt, respectively. Δ<i>pmtA</i> is also more sensitive to streptonigrin, a Fe(II)-activated antibiotic. Furthermore, growth defects of Δ<i>pmtA</i> under Fe(II) or Co(II) excess conditions can be alleviated by manganese [Mn(II)] supplementation. Finally, PmtA plays a role in tolerance to H₂O₂-induced oxidative stress, yet is not involved in the virulence of <i>S. suis</i> in mice. Together, these data demonstrate that <i>S. suis</i> PmtA acts as a Fe(II) and Co(II) efflux pump, and contributes to oxidative stress resistance.过渡金属（transition metals）是生命必需的营养物质。然而，金属过量会对细胞产生毒性，而宿主介导的金属毒性是控制细菌感染的重要机制。因此，细菌进化出了金属外排系统以维持金属稳态（metal homeostasis）。本研究证实，PmtA在猪链球菌（*Streptococcus suis*）中作为亚铁离子[Fe(II)]与钴离子[Co(II)]的外排泵发挥功能；猪链球菌是一种新兴的人畜共患病原体，可引发人类与猪的重症感染。*pmtA*的表达可被Fe(II)、Co(II)与镍离子[Ni(II)]诱导，而PmtA可保护猪链球菌免受Fe(II)及三价铁[Fe(III)]介导的杀菌作用，以及Co(II)与锌离子[Zn(II)]介导的抑菌作用。在高浓度Fe(II)与Co(II)环境中，ΔpmtA突变株的胞内铁与钴离子水平分别显著升高。ΔpmtA突变株对链黑菌素（一种Fe(II)激活的抗生素）的敏感性也更高。此外，在Fe(II)或Co(II)过量的条件下，通过添加锰离子[Mn(II)]可缓解ΔpmtA突变株的生长缺陷。最后，PmtA可参与抵御过氧化氢（H₂O₂）介导的氧化应激，但并不影响猪链球菌在小鼠体内的毒力。综上，本研究结果表明，猪链球菌PmtA作为Fe(II)与Co(II)的外排泵发挥功能，并可增强菌体对氧化应激的耐受性。