Research
The overarching goal of the Mayers Lab is to decipher the key metabolic pathways active in patients that contribute to pathophysiology in diseases caused by microbes. We do this by creating and utilizing workflows that highlight prominent metabolic behaviors in patient samples in disease and assign responsibility for these activities to either the host or microbe (or a combination). We then take these observations and mechanistically investigate the roles of the highlighted metabolism in models using a a mix of biochemistry, genetics and chemical biology.
Deciphering Metabolism in AMR-Associated Infections
Antimicrobial resistance (AMR) is an escalating public health crisis disproportionately affecting less developed areas of the world and immunocompromised patients everywhere. Our ability to treat resistant infections, however, has been slowed by a limited target repertoire and difficulties identifying new options that translate in vivo. Indeed, disrupting metabolism is one potentially attractive direction that has largely failed to make this transition from bench to bedside. We have started to address this opportunity using untargeted metabolomics in patient samples, which offers the potential to discover new or uncommon metabolism linked with disease. Traditional approaches to untargeted metabolomics, however, face technical challenges that limit our throughput to ultimately define these metabolic activities. We have therefore developed a comparative metabolomics pipeline that provides a rational, biologically informative set of filters to speed up this process and are using it to investigate bloodstream infections (BSI), a leading cause of AMR-associated death. We are also working to link our metabolomics data with sequencing data, generating integrated multi-omics datasets, to further accelerate this discovery process. Longer term, we are interested applying our approaches to other leading causes of AMR-associated deaths beyond BSI.
Investigating Metabolism in the Microbiome of Structural Lung Disease
Microbial metabolism in high biomass microbiomes like the gut impacts human health and disease via metabolic signaling, shared metabolic pathways, toxin production, and drug metabolism. How or if these connections apply in lower biomass microbiomes such as the lung remains unclear. We know that the ability of the lung to clear microbes is disrupted in structural lung disease, enabling the development of chronic resident microbial communities. Studies in chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and lung cancer have correlated microbiome level losses in diversity and increases in burden with disease progression. However, we lack mechanistic studies linking specific microbial behaviors like metabolism to disease, which are the essential next step to enable interventions. Probing these functional connections requires expanding into multi-omics techniques that are just now being applied to this space. We are working to acquire these datasets in patient samples and models and to investigate potential links experimentally. We have a particular interest connecting our observations to the process of progression from premalignant states like COPD and IPF to invasive cancer.
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