Loss of CsrA in Acinetobacter baumannii leads to lethal dysregulation of alanine metabolism.

Authors

Rosa L Sava, Michael J Gebhardt

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 40. Pages e2624702123. Oct 06, 2026. Epub Sep 29, 2026.

Abstract

Posttranscriptional regulation is a key mechanism by which bacteria coordinate gene expression in response to changing environments. In the human pathogen Acinetobacter baumannii, the importance of posttranscriptional gene expression control is exemplified by CsrA, a highly conserved posttranscriptional regulator that is essential for viability in multiple settings, ranging from growth in rich laboratory media to infection-relevant conditions like human serum. However, csrA is dispensable for growth in chemically defined media with a single carbon source. We leveraged this condition-specific essentiality to identify suppressor mutations that regained the ability to grow in rich media. These analyses identified Lrp, a transcription factor that regulates hundreds of genes in A. baumannii. Among the Lrp regulon, we identified a four gene locus involved with uptake and utilization of D-alanine. We determined that two transcripts encoded by this locus, dadA and cycA2, are repressed by CsrA. The absence of csrA leads to overexpression of both dadA and cycA2, which is toxic, even in wild type A. baumannii. In the csrA mutant, this dysregulation contributes to impaired cell envelope integrity and increased sensitivity to several clinically relevant cell-wall targeting antibiotics, including carbapenems. Collectively, our data indicate that Lrp and CsrA coordinately balance expression of D-alanine utilization genes in A. baumannii, at the transcriptional and posttranscriptional levels, respectively. Moreover, it appears that a key aspect of CsrA's essentiality in A. baumannii is to counter the activities of Lrp, a second global regulator. These findings further highlight the complex interplay between transcriptional and posttranscriptional regulators in bacteria.

PMID:
42809404
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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