Biology subjects

Sorensen, J. L.

Publications and source records attributed to Sorensen, J. L..

3 recordsLinked to original sources

bioRxiv2026

An activity-resistance tradeoff constrains enzyme evolution

The presence of self-resistance genes in antibiotic-producing organisms poses a paradox: how can resistance evolve before the antibiotic exists, and how can an antibiotic producer arise without first evolving resistance? Here we examine the evolutionary origins of self-resistance to mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH). The MPA biosynthetic gene cluster (BGC) includes a resistant IMPDH-B. Homologs of IMPDH-B occur not only in MPA producers but also in many non-producing fungi, where remnants of the MPA BGC remain detectable. The phylogeny of IMPDH-B is incongruent with the fungal species tree, consistent with multiple horizontal gene transfer events between Aspergillus and Sordariomycetes. We characterized eleven extant IMPDH-Bs, five from MPA producers and six from nonproducers, along with seven resurrected ancestral enzymes (Anc1-Anc7). MPA resistance appeared between Anc2 and Anc3 and coincided with a loss of catalytic efficiency. Across both ancestral and extant enzymes, MPA resistance correlated strongly with reduced activity, revealing a robust activity-resistance trade-off that has persisted for millions of years. Unexpectedly, both the IMPDH-Bs and ancestral enzymes Anc3-Anc7 were also resistant to ribavirin-5'-monophosphate (RVP), an IMP-competitive inhibitor. Because MPA and RVP bind to similar enzyme conformations, the activity-resistance trade-off likely reflects a design constraint imposed by the need to maintain resistance to multiple inhibitors. Intriguingly, although Anc1 and Anc2 are equally sensitive to MPA, Anc2 shows reduced susceptibility to RVP. This pattern suggests that pre-existing resistance to another IMPDH inhibitor may have created a permissive background for the later evolution of MPA biosynthesis. SignificanceAntibiotic producers must be resistant to the toxins that they produce, but how such self-resistance develops is a mystery. The mycophenolic acid (MPA) biosynthetic gene cluster (BGC) encodes a resistant variant of the MPA target IMPDH (IMPDH-B). Many fungi retain IMPDH-B although they have lost the ability to produce MPA. The IMPDH-B and species phylogenies are incongruent, suggesting evolution of the BGC was complicated. MPA resistance correlates with low catalytic efficiency in modern and ancestral IMPDHs, revealing a robust design constraint tradeoff. Surprisingly, IMPDH-Bs are also resistant to an IMP-competitive inhibitor (RVP). RVP resistance appears to have emerged before MPA resistance. Perhaps resistance to RVP created a background that permitted the genesis of a new toxin.

evolutionary biology↗

bioRxiv2025

Wheat infection by Fusarium graminearum species complex members is facilitated by a transcriptionally conserved non-ribosomal peptide synthetase gene cluster

Biosynthetic gene clusters (BGCs) are often found in fungal pathogens and encode secondary (or specialized) metabolites that play crucial roles in host and niche adaptation. However, the regulatory dynamics and functions of these BGCs during host infection remain largely unknown. To address this gap, we employed interspecies comparative transcriptomics to identify BGCs involved in host-pathogen interactions mediated by the Fusarium graminearum species complex (FGSC). We conducted joint transcriptomic and metabolomic analyses during wheat infection and in vitro experiments with five members of the FGSC to understand gene regulation during host infection. Our findings revealed that expression regulation was predominantly species-specific, but we also identified a set of shared upregulated genes that were common to all five FGSC species showing enrichment for metabolic and pathogenicity-associated functions. We focused on jointly upregulated BGC during infection and identified a NRPS-like gene cluster named SM3. The cluster was highly conserved within FGSC and shared by the more distant F. sambucinum species complex. We show that inactivation of the BGC core gene significantly impairs F. graminearum sensu stricto (s.s.) spore production, reduces fungal spread and Fusarium Head Blight symptoms on wheat kernels. Our results highlight that comparative infection transcriptomes can reveal conserved metabolic functions mediating the host infection process of a plant pathogen.

microbiology↗

bioRxiv2019

Phenylacetyl-CoA, not phenylacetic acid, mediates quorum sensing-regulated virulence in Burkholderia cenocepacia

During phenylalanine catabolism, phenylacetic acid (PAA) is converted to phenylacetyl-CoA (PAA-CoA) by a ligase, PaaK, and then epoxidized by a multicomponent monooxygenase, PaaABCDE, before further degradation to the TCA cycle. In the opportunistic pathogen Burkholderia cenocepacia, loss of paaABCDE attenuates virulence factor expression, which is under control of the LuxIR-like quorum sensing system, CepIR. To further investigate the link between CepIR-regulated virulence and PAA catabolism, we created knockout mutants of the first step of the pathway (PAA-CoA synthesis by PaaK) and characterized them in comparison to a paaABCDE mutant using liquid chromatography/mass spectrometry (LC-MS/MS) and virulence assays. We found that while loss of PaaABCDE decreased virulence, deletion of the paaK genes resulted in a more virulent phenotype than the wild type strain. Deletion of either paaK or paaABCDE led to higher levels of released PAA but no differences in internal accumulation, compared to wild type. While we found no evidence of direct cepIR downregulation by PAA-CoA or PAA, a low virulence cepR mutant reverted to a virulent phenotype upon removal of the paaK genes. On the other hand, removal of paaABCDE in the cepR mutant did not impact its attenuated phenotype. Together, our results suggest an indirect role for PAA-CoA in supressing B. cenocepacia CepIR-activated virulence.\n\nImportanceThe opportunistic pathogen Burkholderia cenocepacia uses a chemical signal process called quorum sensing (QS) to produce virulence factors. In B. cenocepacia, QS relies on the presence of the transcriptional regulator CepR, which upon binding QS signal molecules, activates virulence. In this work, we found that even in the absence of CepR, B. cenocepacia can elicit a pathogenic response if phenylacetyl-CoA, an intermediate of the phenylacetic acid degradation pathway, is not produced. Instead, accumulation of phenylacetyl-CoA appears to attenuate pathogenicity. Therefore, we have discovered that it is possible to trigger virulence in the absence of CepR, challenging the classical view of activation of virulence by this QS mechanism. Our work provides new insight into the relationship between metabolism and virulence in opportunistic bacteria. We propose that, in the event that QS signaling molecules cannot accumulate to trigger a pathogenic response, a metabolic signal can still activate virulence in B. cenocepacia.

microbiology↗