MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake

Abstract

MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake co-ordinated regulation of metal ion homeostasis and oxidative stress resistance via the regulators MntR, PerR and Fur of S. aureus is discussed. IntroductionThe acquisition of metal ions is essential for the life of all organisms. During bacterial infection, the host restricts the availability of some metal ions, such as iron. With the exception of Borrelia burgdorferi (Posey and Gherardini, 2000), successful colonization requires that pathogenic bacteria overcome this iron limitation (Wooldridge and Williams, 1993). Although B. burgdorferi does not need iron, it has an obligate requirement for manganese (Mn) (Posey and Gherardini, 2000). Manganese uptake has recently been shown to be important for a number of other pathogens. Bacterial Nramp homologues, called MntH, are selective Mn transporters that play a role in the response to reactive oxygen species and may have a role in pathogenesis (Kehres et al., 2000;Makui et al., 2000). In addition, the ATP-binding cassette (ABC) family of Mn transporters (Claverys, 2001) was clearly shown to be important during infections caused by Enterococcus faecalis (Singh et al., 1998), Streptococcus pneumoniae and Streptococcus parasanguinis (Burnette-Curley et al., 1995;Berry and Paton, 1996) and Yersinia pestis (Bearden and Perry, 1999). Thus, Mn can be added to the in vivo growth requirements of many pathogens (Posey and Gherardini, 2000).In bacteria, specific cellular roles have been determined for Mn as a cofactor in enzymes for metabolism, catabolism, signal transduction and photosynthesis (reviewed by Yocum and Pecoraro, 1999;Jakubovics and Jenkinson, 2001). In addition, an enzymatic and a non-enzymatic role for Mn in the protection of the cell from oxidative stress has been described. Many bacteria, including Staphylococcus aureus (Clements et al., 1999;Valderas and Hart, 2001), contain a Mn-superoxide dismutase (SOD) that catalyses the reduction of superoxide radicals to produce H 2 O 2 . Furthermore, inactivation of sodA, which encodes Mn-SOD, reduces virulence of Strep. pneumoniae in a murine intranasal infection (Yesilkaya et al., 2000).Simple Mn(II) salts are known to catalyse the dismutation of superoxide radical (Archibald and Fridovich, 1981a,b;. A number of bacteria have been shown SummaryThe Staphylococcus aureus DtxR-like protein, MntR, controls expression of the mntABC and mntH genes, which encode putative manganese transporters. Mutation of mntABC produced a growth defect in metal-depleted medium and increased sensitivity to intracellularly generated superoxide radicals. These phenotypes resulted from diminished uptake of manganese and were rescued by the addition of excess Mn(II). Resistance to superoxide was incompletely rescued by Mn(II) for STE035 (mntA mntH), and the strain had reduced virulence in a murine abscess model of infection. Expression of mntABC was repressed by Mn(II) in an MntR-dependent manner, which cont...

Catalase (KatA) and Alkyl Hydroperoxide Reductase (AhpC) Have Compensatory Roles in Peroxide Stress Resistance and Are Required for Survival, Persistence, and Nasal Colonization inStaphylococcus aureus

“…S. aureus was grown in BHI (Oxoid), Chelex-treated BHI (CT-BHI), or CLR minimal medium at 37°C with shaking at 250 r.p.m. CLR and CT-BHI were prepared as described by Horsburgh et al (17,19). Experimental 25-ml cultures in acid-washed 250-ml flasks were incubated at a starting optical density at 600 nm (OD 600 ) of 0.01, unless otherwise stated, before growth at 37°C.…”

“…The protein concentration was measured using the method of Bradford, with bovine serum albumin as the standard (7). Screening for sensitivity to paraquat, sodium nitroprusside (SNP), SNP plus paraquat, diamide, and tellurite was performed by disk diffusion assay, as described previously (19), using CT-BHI agar without MnSO 4 . The following amounts of each stress compound were used: 50 l of 3 M paraquat, 50 l of 1 M SNP, 50 l of a 50:50 mixture of 3 M paraquat and 1 M SNP, 25 l of 1 M diamide, and 25 l of 1 M potassium tellurite.…”

“…The presence of Mn(II) may therefore reduce the requirement for the PerR-controlled antioxidant proteins. In S. aureus, Mn(II) uptake is mediated by the MntABC and MntH transporters, which are regulated by MntR (19). MntR is an Mn(II)-dependent regulator of transcription.…”

Cellular Defenses against Superoxide and Hydrogen Peroxide

“…However, the regulation of manganese importers is slightly at odds with this model: the proton-driven manganese importer MntH is induced (by OxyR) when E. coli is exposed to H 2 O 2 (141), not O 2 − -and the ATP-driven importer MntABC is induced in Stapholococcus aureus under the same circumstances by its PerR system (142). Further, mutations that eliminate these systems sensitize a variety of microbes to H 2 O 2 (143) (141).…”

A manganese transporter, BB0219 (BmtA), is required for virulence by the Lyme disease spirochete, Borrelia burgdorferi

“…but does accumulate Mn (Mn accumulation was severely impaired in the bmtA mutant), (ii) Mn is believed to be involved in the oxidative stress response of a number of pathogens (17,31,32), and (iii) Bb SodA (BB0153) has been predicted to be Mn-dependent (22, 33), we explored whether the inactivation of bmtA adversely impacted Bb's ability to detoxify intracellular superoxide. When WT 297 was exposed to 5 mM or 10 mM t-butyl hydroperoxide, Ϸ100% or 93%, respectively, of the cells survived (Fig.…”