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Focusing on Gen as a viable alternative antibiotic for the treatment of gonorrheal infections, we used RNA-seq to determine if sub-lethal levels of Gen might impact gonococci on a transcriptional level. We found that sub-lethal Gen levels altered the expression of 23 genes in Ng strain FA19. Many of the differentially regulated genes were associated with known stress responses elaborated by Ng under different harmful conditions. We found that the transcripts of the\n                      <jats:italic toggle=\"yes\">hicAB<\/jats:italic>\n                      operon, which encodes a putative HicA-HicB toxin-antitoxin system that is encoded by tandem genes with the prophage Ngo \u03c63, were increased in response to Gen. Although the loss of\n                      <jats:italic toggle=\"yes\">hicAB<\/jats:italic>\n                      did not impact gonococcal susceptibility to a variety of antimicrobial agents or harmful environmental conditions, it did reduce biofilm formation in Ng strains F62, FA1090, WHO X, and CDC200 but not that of strain FA19. Furthermore, in strain F62, but not FA19, loss of\n                      <jats:italic toggle=\"yes\">hicAB<\/jats:italic>\n                      reduced the\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      fitness of Ng during experimental lower genital tract infection of female mice. Furthermore, we found that expression of\n                      <jats:italic toggle=\"yes\">hicAB<\/jats:italic>\n                      can influence levels of the\n                      <jats:italic toggle=\"yes\">norB<\/jats:italic>\n                      transcript\n                      <jats:italic toggle=\"yes\">,<\/jats:italic>\n                      which encodes the nitrate reductase shown previously to be upregulated in gonococcal biofilms. We propose that sub-lethal Gen has the capacity to influence gonococcal pathogenesis through the action of the HicAB toxin-antitoxin system.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      During antibiotic treatment, bacteria can be exposed to sub-lethal levels that could serve as a stress signal, resulting in changes in gene expression. The continued emergence of multi-drug-resistant strains of Ng has rekindled interest in expanded use of gentamicin (Gen) for the treatment of gonorrheal infections. We report that sub-lethal levels of Gen can influence levels of Ng transcripts, including that of the gonococcal\n                      <jats:italic toggle=\"yes\">hicAB<\/jats:italic>\n                      -encoded toxin-antitoxin (TA) locus, which is embedded within an integrated prophage. Although the loss of this TA locus did not impact Ng susceptibility to Gen, it reduced the biofilm-forming ability of four of five Ng strains. Furthermore, in an examined strain in this group, we found that Ng fitness during experimental infection was negatively impacted. We propose that levels of the\n                      <jats:italic toggle=\"yes\">hicA-hicB<\/jats:italic>\n                      transcripts can be increased by sub-lethal levels of an antibiotic used in the treatment of gonorrhea and that this could influence pathogenicity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01595-25","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T13:00:38Z","timestamp":1753880438000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Gentamicin induction of the gonococcal\n                    <i>hicAB<\/i>\n                    toxin-antitoxin-encoding system and impact on gene expression influencing biofilm formation and\n                    <i>in vivo<\/i>\n                    fitness in a strain-specific manner"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0177-4270","authenticated-orcid":false,"given":"Concerta L.","family":"Holley","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01pbhra64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijaya","family":"Dhulipala","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01pbhra64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Le Van","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04r3kq386","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Uniformed Services University","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline T.","family":"Balthazar","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01pbhra64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent J.","family":"Oliver","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04r3kq386","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Uniformed Services University","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann E.","family":"Jerse","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04r3kq386","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Uniformed Services University","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9303-8777","authenticated-orcid":true,"given":"William M.","family":"Shafer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01pbhra64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta, USA"]},{"id":[{"id":"https:\/\/ror.org\/02gars961","id-type":"ROR","asserted-by":"publisher"}],"name":"The Emory Antibiotic Resistance Center, Emory University School of Medicine","place":["Atlanta, USA"]},{"id":[{"id":"https:\/\/ror.org\/04r3kq386","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center","place":["Decatur, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_6_2_2","unstructured":"Centers for Disease Control and Prevention. 2019. 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