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Although this coordination is essential for survival, the molecular mechanisms linking OM and PG homeostasis remain poorly understood. LD-transpeptidases (LDTs) are enzymes that crosslink peptides in PG and incorporate\n                      <jats:sc>d<\/jats:sc>\n                      -amino acids, but their physiological roles are not fully defined. Here, we characterize the activity of the LDT enzyme LdtJ in\n                      <jats:italic toggle=\"yes\">Acinetobacter baumannii<\/jats:italic>\n                      and investigate the consequences of its deletion. Loss of LdtJ disrupts cell morphology, downregulates PG precursor genes (e.g.,\n                      <jats:italic toggle=\"yes\">dadA<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">alr<\/jats:italic>\n                      ), and activates the stringent response, including elevated ppGpp levels and\n                      <jats:italic toggle=\"yes\">dksA<\/jats:italic>\n                      upregulation. These defects are fully suppressed in a \u2206\n                      <jats:italic toggle=\"yes\">ldtJ<\/jats:italic>\n                      \u2206\n                      <jats:italic toggle=\"yes\">mla<\/jats:italic>\n                      double mutant, implicating the OM lipid transport Mla pathway in compensatory regulation. RNA sequencing revealed that transcriptional changes in the \u2206\n                      <jats:italic toggle=\"yes\">ldtJ<\/jats:italic>\n                      mutant are reversed in the double mutant, highlighting a functional interplay between PG remodeling and OM lipid asymmetry. Our findings suggest that LdtJ contributes to envelope integrity not only through PG modification but also by influencing broader regulatory and metabolic networks.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Acinetobacter baumannii<\/jats:italic>\n                        is a leading cause of hospital-acquired infections and is highly resistant to antibiotics. Its survival relies on the integrity of the cell envelope, composed of the peptidoglycan (PG) layer and outer membrane (OM). While LD-transpeptidases are traditionally known for reinforcing PG structure through non-canonical crosslinking, our findings reveal that the LdtJ enzyme also plays a critical role in regulating cellular metabolism and stress responses. Deletion of\n                        <jats:italic toggle=\"yes\">ldtJ<\/jats:italic>\n                        results in pronounced growth defects and abnormal cell morphology\u2014phenotypes that are fully suppressed by disrupting the OM lipid asymmetry transport system, Mla. This genetic interaction uncovers a previously unrecognized link between PG remodeling and OM lipid homeostasis. These insights deepen our understanding of envelope coordination in Gram-negative bacteria.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00331-25","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T13:18:14Z","timestamp":1758201494000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Molecular interplay between peptidoglycan integrity and outer membrane asymmetry in maintaining cell envelope homeostasis"],"prefix":"10.1128","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1348-0879","authenticated-orcid":false,"given":"Sinjini","family":"Nandy","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049emcs32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences, The University of Texas at Dallas","place":["Richardson, 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