{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:42:51Z","timestamp":1791852171708,"version":"4.3.4"},"reference-count":90,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      relies on the (p)ppGpp-mediated stringent response to adapt to nutrient limitation and other environmental stress, with important consequences for metabolism, antibiotic tolerance, and virulence. In this study, we identified that disruption of (p)ppGpp synthesis altered the small RNA (sRNA) cargo of extracellular vesicles (EVs) produced by\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      . We characterized EV-associated sRNAs from wild-type and stringent response mutant (\n                      <jats:italic toggle=\"yes\">rsh<\/jats:italic>\n                      <jats:sub>syn<\/jats:sub>\n                      ) strains, revealing the presence of SprX2 in mutant EVs. The\n                      <jats:italic toggle=\"yes\">rsh<\/jats:italic>\n                      <jats:sub>syn<\/jats:sub>\n                      mutant also showed modestly enhanced survival under high concentrations of vancomycin and oxacillin in late stationary phase. Transcriptomic analysis under mupirocin-induced amino acid limitation demonstrated broad ppGpp-dependent remodeling of gene expression, including changes in amino acid biosynthesis, translation-associated functions, adhesion factors, and virulence-associated genes. Treatment with the synthetic cationic peptide DJK-5 reduced intracellular ppGpp levels, suppressed the expression of genes involved in adhesion (\n                      <jats:italic toggle=\"yes\">fnbA<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">fnbB<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">clfB<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">emp<\/jats:italic>\n                      ), cytolytic toxins (\n                      <jats:italic toggle=\"yes\">psm\u03b21<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">psm\u03b22, hla<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">lukED<\/jats:italic>\n                      ), and exoenzymes (\n                      <jats:italic toggle=\"yes\">lip<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">geh<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">sspA<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">aur<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">sspB<\/jats:italic>\n                      ), and reduced methicillin-resistant\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      (MRSA)-mediated toxicity toward eukaryotic cells. These findings suggest that targeting the stringent response impairs both intracellular regulatory networks and EV-mediated signaling, offering a promising approach to attenuate\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      virulence and enhance efficacy against resistant infections.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The stringent response helps\n                        <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                        survive nutrient stress, adapt its metabolism, and regulate virulence. This study shows that disrupting this pathway not only alters intracellular gene expression but is also associated with changes in the small RNA (sRNA) cargo of extracellular vesicles. In addition, the synthetic peptide DJK-5 weakens the pathogen\u2019s ability to regulate biofilm formation, its virulence, and reduces its communication through small RNA molecules, which are critical for stress adaptation and infection. These findings introduce an approach to weakening bacterial defenses and suggest that interfering with stress responses could enhance the effectiveness of existing antibiotics against antibiotic-resistant bacteria, offering a promising strategy for combating bacterial infections and reducing antibiotic resistance.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00359-26","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:01:02Z","timestamp":1781524862000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the stringent response alters gene expression and extracellular vesicle RNA in\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","volume":"14","author":[{"given":"Sarah C.","family":"Mansour","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03rmrcq20","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia","place":["Vancouver, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6886-6933","authenticated-orcid":false,"given":"Samuel J. 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