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Studies have primarily focused on emerging\n                      <jats:italic toggle=\"yes\">H. influenzae<\/jats:italic>\n                      strains with acquired macrolide resistance, while the bacterium\u2019s intrinsic resistance to antibiotics has been underexamined. Here, we used a genome-wide approach of transposon insertion-site sequencing to screen an\n                      <jats:italic toggle=\"yes\">H. influenzae<\/jats:italic>\n                      mutant library grown in sub-inhibitory doses of the macrolide antibiotic clarithromycin (CLR) to identify 33 genes involved in intrinsic CLR resistance. Almost half of these genes are also needed for survival in the mouse lung. We focused on candidate genes necessary for both intrinsic macrolide resistance and lung survival. Two of these genes affect the outer-membrane composition of\n                      <jats:italic toggle=\"yes\">H. influenzae<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">orfH<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">omp26<\/jats:italic>\n                      . Deletions of these genes in Rd and nontypeable\n                      <jats:italic toggle=\"yes\">H. influenzae<\/jats:italic>\n                      clinical isolates, Hi375 and NT127, conferred sensitivity to CLR and polymyxin B and increased membrane permeability to ethidium bromide (EtBr). The\n                      <jats:italic toggle=\"yes\">omp26<\/jats:italic>\n                      mutant was sensitive to killing by human serum. Deletions of\n                      <jats:italic toggle=\"yes\">orfH<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">omp26<\/jats:italic>\n                      in an\n                      <jats:italic toggle=\"yes\">acrR<\/jats:italic>\n                      mutant strain overexpressing a multidrug efflux pump abrogated resistance of the\n                      <jats:italic toggle=\"yes\">acrR<\/jats:italic>\n                      mutant to CLR and restored permeability to EtBr. Thus, deletion of these genes not only mitigates the effects of an acquired resistance mechanism but also remarkably overrides it. Complementation of these deletion mutations restored CLR resistance and decreased permeability to EtBr. Our results indicate that the subset of genes with dual roles in intrinsic resistance and host lung survival may provide potential novel combination antimicrobial therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00369-26","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:03:35Z","timestamp":1786025015000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Dual roles of genes required for intrinsic resistance to clarithromycin in evasion of killing by serum complement in\n                    <i>Haemophilus influenzae<\/i>"],"prefix":"10.1128","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0421-2601","authenticated-orcid":false,"given":"Cameron","family":"Huhn","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044pcn091","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center","place":["Jackson, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Dees","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044pcn091","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center","place":["Jackson, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Gawronski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Physiological Systems, University of Massachusetts Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma Ul","family":"Taslim","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044pcn091","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center","place":["Jackson, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1698-6325","authenticated-orcid":false,"given":"Sandy","family":"Wong","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044pcn091","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center","place":["Jackson, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-7035","authenticated-orcid":true,"given":"Brian","family":"Akerley","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044pcn091","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center","place":["Jackson, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1017\/s0950268800067327"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10050577"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.108.1.1"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31222-9"},{"key":"e_1_3_5_6_2","unstructured":"Association AL. 2025. 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