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The Xenorhabdus nematophila LrhA transcriptional regulator modulates production of γ-keto- N -acyl amides with inhibitory activity against mutualistic host nematode egg hatching
is a symbiotic Gammaproteobacterium that produces diverse natural products that facilitate mutualistic and pathogenic interactions in their nematode and insect hosts, respectively. The interplay between secondary metabolism and symbiosis stage is tuned by various global regulators. An example of suc...
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Published in: | Applied and environmental microbiology 2024-07, Vol.90 (7), p.e0052824 |
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Main Authors: | , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | is a symbiotic Gammaproteobacterium that produces diverse natural products that facilitate mutualistic and pathogenic interactions in their nematode and insect hosts, respectively. The interplay between
secondary metabolism and symbiosis stage is tuned by various global regulators. An example of such a regulator is the LysR-type protein transcription factor LrhA, which regulates amino acid metabolism and is necessary for virulence in insects and normal nematode progeny production. Here, we utilized comparative metabolomics and molecular networking to identify small molecule factors regulated by LrhA and characterized a rare γ-ketoacid (GKA) and two new
-acyl amides, GKA-Arg (
) and GKA-Pro (
) which harbor a γ-keto acyl appendage. A
null mutant produced elevated levels of compound
and reduced levels of compound
relative to wild type.
-acyl amides
and
were shown to be selective agonists for the human G-protein-coupled receptors (GPCRs) C3AR1 and CHRM2, respectively. The CHRM2 agonist
deleteriously affected the hatch rate and length of
nematodes. This work further highlights the utility of exploiting regulators of host-bacteria interactions for the identification of the bioactive small molecule signals that they control.
bacteria are of interest due to their symbiotic relationship with
nematodes and their ability to produce a variety of natural bioactive compounds. Despite their importance, the regulatory hierarchy connecting specific natural products and their regulators is poorly understood. In this study, comparative metabolomic profiling was utilized to identify the secondary metabolites modulated by the
global regulator LrhA. This analysis led to the discovery of three metabolites, including an
-acyl amide that inhibited the egg hatching rate and length of
nematodes. These findings support the notion that
LrhA influences the symbiosis between
and
through
-acyl amide signaling. A deeper understanding of the regulatory hierarchy of these natural products could contribute to a better comprehension of the symbiotic relationship between
and
. |
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ISSN: | 0099-2240 1098-5336 1098-5336 |
DOI: | 10.1128/aem.00528-24 |