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bioRxiv · 10.64898/2026.01.06.698069

Periplasmic proteostasis enables bacterial survival during MreB cytoskeletal disruption

Nagarajan, T.·Nandhakumar, M.·Kannan, B.·Magar, S.·Kannaiah, S.·Amster-Choder, O.·Govindarajan, S.
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Abstract

The bacterial actin homolog MreB is essential for various cellular processes, including cell wall biosynthesis, membrane organization, and cell polarity determination. Given its multifaceted roles, MreB is considered a potential target for antibiotic development. However, the bacterial response to MreB inhibition and the factors contributing to bacterial survival under such conditions are not well understood. In this study, RNA sequencing (RNA-seq) was used to identify genes that are differentially expressed in response to MreB inhibition by the A22 antibiotic or to deletion of the mreBCD operon. We identified 6 upregulated genes and 24 downregulated genes under both conditions. To determine whether the upregulated genes contribute to bacterial survival during MreB inhibition, we performed A22 antibiotic susceptibility assay on mutants deleted for each of the 6 upregulated genes. Our findings reveal that cells lacking DegP, a periplasmic serine protease, are highly suceptible to A22 treatment. Complementation analysis showed that wild-type DegP, but not a protease-defective mutant, mitigated the effects of A22. The morphological defects in DegP-deficient cells caused by A22 were reduced by ectopic expression of related periplasmic proteases, such as DegQ and DegS. Furthermore, elevated temperatures could alleviate the effects of A22 in a DegP-dependent manner. Overall, our study provides a comprehensive analysis of the global transcriptome-wide effects of MreB inhibition, offering new insights into bacterial response to cytoskeleton disruption. The findings highlight the critical role of DegP in bacterial survival during MreB inhibition and suggest potential avenues for developing novel combinatorial antibiotic strategies targeting MreB and DegP. HighlightsO_LIMreB disruption by A22 or mutation causes major transcriptome alterations C_LIO_LISix genes are consistently upregulated under both MreB disruption conditions C_LIO_LIDegP, a periplasmic protease, is crucial for bacterial tolerance to A22 C_LIO_LIElevated temperatures alleviate A22 toxicity in a DegP-dependent manner C_LI

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Nagarajan, T., Nandhakumar, M., Kannan, B., Magar, S., Kannaiah, S., Amster-Choder, O., Govindarajan, S.. 2026-01-07. Periplasmic proteostasis enables bacterial survival during MreB cytoskeletal disruption. https://doi.org/10.64898/2026.01.06.698069

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