Project description:Non-targted MS/MS Natural Product Screening of three bacterial isolates of the genus Pseudomonas, native from agricultural soils in Argentina, that produce surfactant molecules.
Pseudomonas chlororaphis SMMP3
Pseudomonas sp. SVMP4
Pseudomonas sp. SBMP6
Project description:To investigate how a natural product analog mitigates AD, cortical transcriptomes from WT and 5xFAD mice were analyzed. Comparing vehicle-treated groups revealed extensive differential expression associated with neuroinflammation in 5xFAD mice. This was attenuated in the 5xFAD mice treated with the natural product, whose profiles resembled WT controls. RNA seq suggested the natural product regulated the nervous and immune systems.
Project description:TenA-family proteins are widespread bacterial regulators with unknown roles in natural product biosynthesis. This study aimed to functionally characterize LysR2, a TenA-family protein in Actinobacteria, and elucidate its mechanism in regulating the production of lysolipin I. We demonstrate that LysR2 represents a novel type of regulator that controls antibiotic biosynthesis not by direct DNA binding, but through protein-protein interactions, specifically by antagonizing the repressor LysR1. This work reveals an unconventional regulatory strategy, expanding the mechanistic understanding of transcriptional networks in natural product formation.
Project description:Despite significant advancements in drug development and discovery, tuberculosis remains one of the world’s deadliest infectious diseases. The rise and global spread of multidrug-resistant strains underscore a critical need for new antibiotics with distinct mechanisms of action. Screening of a myxobacterial extract library uncovered the previously unrecognized antitubercular activity of corramycin, a natural product with potent bactericidal activity against both drug-sensitive and -resistant Mycobacterium tuberculosis. Corramycin enters the bacterial cell by exploiting multiple transport systems, and induces DNA double-strand breaks through a novel form of DNA gyrase poisoning. The cryo-electron microscopy structure of M. tuberculosis gyrase in complex with corramycin reveals that the natural product targets a site overlapping with the binding site of synthetic fluoroquinolones, thereby locking the gyrase in an inactive conformation and preventing re-ligation of DNA. Importantly, its unique mode of binding allows corramycin to overcome fluoroquinolone resistance, highlighting its promise as a novel antibiotic scaffold to address the antimicrobial resistance crisis.
Project description:Streptomyces has the largest repertoire of natural product biosynthetic gene clusters (BGCs), yet developing a universal engineering strategy for each Streptomyces species is challenging. Given that some Streptomyces species have larger BGC repertoires than others, we hypothesized that a set of genes co-evolved with BGCs to support biosynthetic proficiency must exist in those strains, and that their identification may provide universal strategies to improve the productivity of other strains. We show here that genes co-evolved with natural product BGCs in Streptomyces can be identified by phylogenomics analysis. Among the 597 genes that co-evolved with polyketide BGCs, 11 genes in the “coenzyme” category have been examined, including a gene cluster encoding for the co-factor pyrroloquinoline quinone (PQQ). When the pqq gene cluster was engineered into 11 Streptomyces strains, it enhanced production of 16,385 metabolites, including 36 known natural products with up to 40-fold improvement and several activated silent gene clusters. This study provides a new engineering strategy for improving polyketide production and discovering new biosynthetic gene clusters.
Project description:Natural products represent a rich source for antibiotics addressing versatile cellular targets. The deconvolution of their targets via chemical proteomics is often challenged by the introduction of large photocrosslinkers. Here we select elegaphenone, a largely uncharacterized natural product antibiotic bearing a native benzophenone core scaffold, for affinity-based protein profiling (AfBPP) in Gram-positive and Gram-negative bacteria. This study utilizes the alkynylated natural product scaffold as a probe to uncover intriguing biological interactions with the transcriptional regulator AlgP. Furthermore, proteome profiling of a Pseudomonas aeruginosa AlgP transposon mutant revealed unique insights into the mode of action. Elegaphenone enhanced the killing of intracellular P. aeruginosa in macrophages exposed to sub-inhibitory concentrations of the fluoroquinolone antibiotic norfloxacin.