Rob Smith

The role of bacterial metabolism in antimicrobial resistance Nature Reviews Microbiology - In this Review, Ahmad et al. examine how antibiotics influence bacterial metabolism and how metabolism, in turn, affects drug efficacy and the emergence and evolution...

New review out in @NatureRevMicro on the complex rltnshp btween metabolism & AMR! A true labor of love from previous postbac Mehrose, grad students Varun & Zirui, and collaborator @drrobsmith.bsky.social (plus figures I'll likely use for many talks to come 😊) rdcu.be/eaES2

This work was led by the fantastic Dr. Lauren Krausfeldt, who is currently working with NIAID. This field-to-lab project was challenging and required a ton of perseverance on her part, especially during the social distancing era. I was just happy to be along for the ride.

Overall, these shifts in transcriptome provide us critical information on the activities of Microcystic during bloom and may hint at ways to disrupt bloom intensification and persistence.

Later in the bloom, we found that genes involved in phage protection and toxin production were upregulated. Here, we think Microcystis is activating genes that protect itself against microbial competitors and phage, which may be critical to promoting bloom stability and persistence.

When fed nitrogen, we first saw an increased transcription of genes involved in photosynthesis and nitrogen import. Here, we think Microcystis is working hard to consume as much nitrogen and sunlight as possible to drive the bloom.

We found striking temporal shifts in the transcriptome of Microcystis, which provide insight into how it intensifies and sustains the bloom.

Blooms can often appear ‘out of nowhere’, making the understanding of the transcriptional changes that drive them hard to study. To meet this challenge, we created mesocosms in a river undergoing a bloom. We fed the mesocosms nutrients that drive blooms and measured the transcriptome daily.

In freshwater lakes, the cyanobacteria Microcystis sp. can cause toxic algal blooms that can kill off wildlife, contaminate drinking water, and injure humans. The intensity and frequency of these blooms have been increasing, driven by anthropogenic factors and climate change.

Transcriptional profiles of Microcystis reveal gene expression shifts that promote bloom persistence in in situ mesocosms | Microbiology Spectrum Harmful algal blooms represent a threat to human health and ecosystems. Understanding why blooms persist may help us develop warning indicators of bloom persistence and create novel mitigation strateg...

Harmful algal blooms are a threat to human health. Yet, we don't understand how changes in gene expression of the main culprit, Microcystis, facilitate blooms. Our latest collab, led by Dr. Lauren Krausfeldt and @jochrome1.bsky.social , sheds light on this process. journals.asm.org/doi/full/10....

This study was led by the fantastic undergraduate student Daniella Hernandez, along with an all-star cast of undergraduates, graduates, post-docs, and collaborators, including @ajlopatkin.bsky.social and her team. Congrats to everyone involved!!!

Why this occurs, we don’t know yet, but we are eager to find out. Nevertheless, this work underscores the importance of nucleotide synthesis in determining density-dependent antibiotic resistance

Surprisingly, we found pyrimidine synthesis activity predicts the inoculum effect for aminoglycoside antibiotics, while purine synthesis activity predicts the inoculum effect for B-lactam antibiotics.

We also found that these changes were highly correlated to the strength of the inoculum effect for multiple antibiotics. To develop this further, we examined transcription in purine and pyrimidine synthesis pathways and asked how they could predict changes in the inoculum effect.

This alluded to the role of nucleotide synthesis in the inoculum effect. To test this, we experimentally perturbed nucleotide synthesis in E. coli. We found that this increases bacterial metabolism and reduces growth rate, as predicted in our model.

However, we didn’t know what pathways were responsible. To answer this question, we used an E. coli metabolic model and individually knocked out all of the genes in silico. We found that removing genes in nucleotide synthesis increased metabolism while reducing growth.

Our previous work showed that interactions between bacterial metabolism and growth can explain density-dependent antibiotic resistance, also known as the inoculum effect. When metabolism is greater than growth, bacteria can no longer resist antibiotics using their density.

Purine and pyrimidine synthesis differently affect the strength of the inoculum effect for aminoglycoside and β-lactam antibiotics | Microbiology Spectrum If a bacterial population can grow and reach a sufficiently high density, routine doses of antibiotics can be ineffective. This phenomenon, called the inoculum effect, has been observed for nearly all...

Happy to share our most recent manuscript with the Bsky community.

Bacterial infections that reach a high density are challenging to treat with antibiotics, but we do not know why. We present evidence showing that nucleotide synthesis is intimately involved.

journals.asm.org/doi/10.1128/...

Happy to see the community growing here. Our lab is interested in understanding how bacterial metabolism impacts antibiotic resistance. We often hop into other cool projects outside our primary interest, ranging from understanding algal blooms to identifying quantum events in biological systems.

Thank you!!!

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