{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T04:58:51Z","timestamp":1775883531619,"version":"3.50.1"},"posted":{"date-parts":[[2025,1,16]]},"group-title":"Microbiology","reference-count":131,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The complement cascade is a front-line defense against pathogens. Complement activation generates the membrane attack complex (MAC), a 10-11 nm diameter pore formed by complement proteins C5b through C8 and polymerized C9. The MAC embeds within the outer membrane of Gram-negative bacteria and displays bactericidal activity. In the absence of C9, C5b-C8 complexes can form 2-4 nm pores on membranes, but their relevance to microbial control is poorly understood. Deficiencies in terminal complement components uniquely predispose individuals to infections by pathogenic\n                  <jats:italic>Neisseria,<\/jats:italic>\n                  including\n                  <jats:italic>N. gonorrhoeae<\/jats:italic>\n                  (Gc). Increasing antibiotic resistance in Gc makes new therapeutic strategies a priority. Here, we demonstrate that MAC formed by complement activity in human serum disrupts the Gc outer and inner membranes, potentiating the activity of antimicrobials against Gc and re-sensitizing multidrug resistant Gc to antibiotics. C9-depleted serum also disrupts Gc membranes and exerts antigonococcal activity, effects that are not reported in other Gram-negative bacteria. C5b-C8 complex formation potentiates Gc sensitivity to azithromycin but not lysozyme. These findings expand our mechanistic understanding of complement lytic activity, suggest a size limitation for terminal complement-mediated enhancement of antimicrobials against Gc, and suggest complement manipulation can be used to combat drug-resistant gonorrhea.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    The complement cascade is a front-line arm of the innate immune system against pathogens. Complement activation results in membrane attack complex (MAC) pores forming on the outer membrane of Gram-negative bacteria, resulting in bacterial death. Individuals who cannot generate MAC are specifically susceptible to infection by pathogenic\n                    <jats:italic>Neisseria<\/jats:italic>\n                    species including\n                    <jats:italic>N. gonorrhoeae<\/jats:italic>\n                    (Gc). High rates of gonorrhea and its complications like infertility, and high-frequency resistance to multiple antibiotics, make it important to identify new approaches to combat Gc. Beyond direct anti-Gc activity, we found the MAC increases the ability of antibiotics and antimicrobial proteins to kill Gc and re-sensitizes multidrug-resistant bacteria to antibiotics. The most terminal component, C9, is needed to potentiate the anti-Gc activity of lysozyme, but azithromycin activity is potentiated regardless of C9. These findings highlight the unique effects of MAC on Gc and suggest novel translational avenues to combat drug-resistant gonorrhea.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.16.633325","type":"posted-content","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T01:35:13Z","timestamp":1737077713000},"source":"Crossref","is-referenced-by-count":0,"title":["Terminal complement complexes with or without C9 potentiate antimicrobial activity against\n                  <i>Neisseria gonorrhoeae<\/i>"],"prefix":"10.64898","author":[{"given":"Evan R.","family":"Lamb","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7738-3757","authenticated-orcid":false,"given":"Alison K.","family":"Criss","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041021381491000_2025.01.16.633325v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13760"},{"key":"2026041021381491000_2025.01.16.633325v1.2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00048-09"},{"key":"2026041021381491000_2025.01.16.633325v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2021.09.002"},{"key":"2026041021381491000_2025.01.16.633325v1.4","doi-asserted-by":"crossref","unstructured":"Hastings CJ , Syed SS , Marques CNH . 2023. 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