How Staphylococcus aureus Exploits a Host Metabolite to Cause Pneumonia
- Ray Sullivan
- Aug 11
- 3 min read

Staphylococcus aureus is a formidable foe in healthcare settings, a leading cause of pneumonia that contributes significantly to illness and death worldwide. This ubiquitous bacterium, a common colonizer of the upper respiratory tract, demonstrates remarkable metabolic flexibility, allowing it to adapt and persist in the lung's unique microenvironment. An international collaboration led by Tania Wong, Rutgers Center for Immunity & Inflammation, sheds light on a previously unappreciated mechanism of its adaptation: the manipulation of the host metabolite fumarate through its own enzyme, FumC.
During infection, host macrophages produce fumarate, a potent pro-inflammatory metabolite that normally helps limit inflammation. However, the sources reveal that fumarate accumulates in the chronically infected lung, as seen in patients with cystic fibrosis, where levels are substantially elevated compared to healthy individuals.
For S. aureus, this accumulating fumarate presents a challenge. The metabolite is actually detrimental to the bacteria, blocking primary metabolic pathways vital for energy production, such as glycolysis and oxidative phosphorylation, and disrupting the TCA cycle. It can also directly modify bacterial proteins, including those involved in antioxidative stress responses and iron-sulfur cluster assembly, further impairing bacterial processes.
The new findings by Chen et al. highlight the pivotal role of the bacterial enzyme FumC in navigating this hostile environment. FumC, the gene encoding this enzyme, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections, suggesting its critical importance for pulmonary adaptation and epidemiological significance.
So, how does FumC help S. aureus?
FumC is a fumarate hydratase. It converts the detrimental fumarate into malate, effectively circumventing fumarate's toxic effects.
Beyond just degradation, FumC is a metabolic hub that directs fumarate’s utilization into critical biosynthetic pathways, including:
TCA cycle.
Gluconeogenesis.
Hexosamine synthesis, which is essential for forming a protective biofilm.
Pentose phosphate pathway (PPP), supporting the synthesis of nucleotides (e.g., ATP, NADH) crucial for energy production and survival.
When S. aureus is exposed to fumarate, the presence of FumC is crucial for the expression of genes important in pathogenesis, including those linked to toxin production and capsule production. It also supports antioxidative defenses.
In contrast, a ΔfumC mutant (lacking the FumC enzyme) displays significant growth defects in simulated airway conditions and is more susceptible to oxidative stress. It also shows a downregulation of biofilm-associated genes and virulence factors.
The importance of FumC was further underscored in mouse models of pneumonia. In environments with high fumarate levels, such as in Ptenl−/− mice, the ΔfumC mutant exhibited significant attenuation compared to the wild-type strain. This suggests that FumC is critical for S. aureus survival in conditions mimicking chronic lung infections.
Interestingly, S. aureus doesn't just rely on its own FumC. The group’s research indicates that the bacterium can exploit host fumarate hydratase (FH) to mitigate the absence of fumC in vivo. This means the host's own enzyme can, to some extent, degrade fumarate and limit its detrimental effects on the bacteria, allowing them to proliferate even without their own FumC.
Furthermore, another abundant immunometabolite found in infected airways, itaconate, shares structural similarities with fumarate and was found to enhance FumC activity, promoting fumarate degradation and utilization. This suggests a synergistic interaction between these host metabolites that further aids S. aureus adaptation.
Given the pivotal role of FumC in S. aureus adaptation and persistence in the lung, these findings open the possibility of selectively targeting staphylococcal FumC to prevent chronic airway infection. While both human and S. aureus fumarate hydratase share structural similarities, distinct features of the bacterial FumC may allow for the development of selective inhibitors, offering a novel approach to combat S. aureus pneumonia, especially given the past failures of vaccine strategies targeting classic virulence factors. This research highlights the critical importance of understanding bacterial metabolic adaptation in the quest for new anti-infective therapies.
Chen YT, Liu Z, Fucich D, Giulieri SG, Liu Z, Wadhwa R, Rios G, Henschel H, Tyagi N, Olivier FAB, Monk IR, Shah SS, Sridhar SH, Drikic M, Bianco C, Lohia GK, Beg AZ, Planet PJ, Lewis IA, Sebra R, Traven A, Hachani A, Stinear TP, Howden BP, Boyd JM, Riquelme SA, Wang C, Prince A, Wong Fok Lung T. Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia. Nat Commun. 2025 Aug 1;16(1):7050. doi: 10.1038/s41467-025-62453-y. PMID: 40745169; PMCID: PMC12313914.
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