# The Metabolic Evolution of Staphylococcus aureus

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $386,838

## Abstract

Abstract.
Methicillin Resistant Staphylococcus aureus (MRSA) is an important human pathogen that exerts a
tremendous negative impact on human health. S. aureus stands out among other species of Coagulase-
Negative Staphylococci (CoNS) in that S. aureus specifically has evolved high pathogenic potential. Some of
this is explained by the arsenal of virulence traits present in the genomes of MRSA isolates. However, the
metabolic evolution of S. aureus contributes equally to the success of this pathogen. That is, S. aureus has
evolved to thrive at sites if inflammation, which are very often hypoxic, replete with immune radicals (e.g. nitric
oxide, NO·) and devoid of free iron. All these attributes limit bacterial respiration and S. aureus has evolved to
better deal with such respiratory stress than most CoNS. In response to respiratory stress, S. aureus elicits a
metabolic state that maximizes glycolytic flux coupled to lactate excretion. This Warburg-like metabolism is
reminiscent of that employed by host immune cells infiltrating to sites if infection. Thus, S. aureus must
compete with the host for available glucose. As such, S. aureus encodes three glucose-specific transporters
not present in most CoNS. Moreover, S. aureus encodes a unique lactate dehydrogenase (Ldh1) that supports
redox balance in the absence of respiration. Our LC-MS metabolomics survey of S. aureus under respiratory
stress has uncovered many new pathways beyond lactate production that contribute to redox balance. Aim 1 of
this proposal seeks to identify the genes that encode the enzymes in these pathways as none have been
annotated. We hypothesize that many of these genes share a common regulatory mechanism and are not
encoded in the genomes of most CoNS. Thus, these newly acquired metabolic genes represent additional
examples of the metabolic evolution that allowed for the emergence of a pathogen from a genus of skin
commensals. We will also explore whether the certain genes exhibit signatures of forward selection specifically
among NO·-resistant staphylococci possibly highlighting new mechanisms of metabolic evolution. The second
Aim focuses on uncovering the mechanism by which all of these newly acquired metabolic genes, and major
virulence regulons (Agr) are controlled by the presence of glucose. We contend that S. aureus uses glucose as
a signal that it has penetrated into deeper tissue given that carbohydrates are scarce on the skin surface.
Coordinating the expression of virulence genes as well as metabolic genes that contribute to growth in
inflamed tissue with the availability of glucose underscores the importance of this carbon source to the
metabolic evolution of S. aureus. As such, the final aim investigates whether excessive blood glucose in
diabetic patients drives MRSA virulence factor production thereby worsening infection. In total, this proposal
seeks to finalize our understanding of the metabolic evolution of an important human pathogen and how it is
intricat...

## Key facts

- **NIH application ID:** 9985701
- **Project number:** 5R01AI093613-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Anthony R. Richardson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,838
- **Award type:** 5
- **Project period:** 2011-03-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985701

## Citation

> US National Institutes of Health, RePORTER application 9985701, The Metabolic Evolution of Staphylococcus aureus (5R01AI093613-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985701. Licensed CC0.

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