Influence of Iron and Aeration on Staphylococcus aureus Growth, Metabolism, and Transcription

Abstract

Staphylococcus aureus is a prominent nosocomial pathogen and a major cause of biomaterial-associated infections. The success of S. aureus as a pathogen is due in part to its ability to adapt to stressful environments. As an example, the transition from residing in the nares to residing in the blood or deeper tissues is accompanied by changes in the availability of nutrients and elements such as oxygen and iron. As such, nutrients, oxygen, and iron are important determinants of virulence factor synthesis in S. aureus. In addition to influencing virulence factor synthesis, oxygen and iron are critical cofactors in enzymatic and electron transfer reactions; thus, a change in iron or oxygen availability alters the bacterial metabolome. Changes in metabolism create intracellular signals that alter the activity of metabolite-responsive regulators such as CodY, RpiRc, and CcpA. To assess the extent of metabolomic changes associated with oxygen and iron limitation, S. aureus cells were cultivated in iron-limited medium and/or with decreasing aeration, and the metabolomes were examined by nuclear magnetic resonance (NMR) spectroscopy. As expected, oxygen and iron limitation dramatically decreased tricarboxylic acid (TCA) cycle activity, creating a metabolic block and significantly altering the metabolome. These changes were most prominent during post-exponential-phase growth, when TCA cycle activity was maximal. Importantly, many of the effects of iron limitation were obscured by aeration limitation. Aeration limitation not only obscured the metabolic effects of iron limitation but also overrode the transcription of iron-regulated genes. Finally, in contrast to previous speculation, we confirmed that acidification of the culture medium occurs independent of the availability of iron.

Redox Imbalance Underlies the Fitness Defect Associated with Inactivation of the Pta-AckA Pathway in Staphylococcus aureus

“…27–32 Consistent with these studies, we detected higher levels of intracellular lactate in all bacteria by 2D 1 H- 13 C HSQC NMR during anaerobiosis (Fig 3A and B). However, when compared to the wild-type strain, we observed decreased concentrations of intracellular lactate in the pta and ackA mutants under fermentative growth (Fig 3A).…”

“…10, 30, 32, 38, 39 We have previously shown that under these conditions the Pta-AckA pathway plays an indispensable role in maintenance of S. aureus fitness, as its inactivation results in growth defects and cell death. Although the precise reasons for the observed defects in growth and viability of pta and ackA mutants are not clearly understood, a role for ATP production (a byproduct of the Pta-AckA pathway) was ruled out earlier.…”

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

“…To modulate the concentration of dioxygen in the culture medium, we varied the ratio of liquid medium volume to culture vessel to gaseous headspace (HV ratio). The higher the HV ratio, the higher the concentration of dissolved dioxygen (34). The sodA::Tn mutant had decreased AcnA activity when cultured at an HV ratio of 20, but the AcnA activity was comparable to that of the WT when cultured at an HV ratio of 2.5 (Fig.…”

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

“…and small putative FeoC-like proteins are encoded within the feo gene cluster in these organisms (Cartron et al, 2006). The Staphylococcus aureus feoAB(C) locus is upregulated during iron starvation in a Furdependent manner (Lin et al, 2012;Ledala et al, 2014).…”