Terminal complement complexes with or without C9 potentiate antimicrobial activity against <i>Neisseria gonorrhoeae</i>

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 <i>Neisseria</i> species including <i>N. gonorrhoeae</i> (Gc). High rates of gonorrhea, 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 that 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 and nisin, but azithromycin and ceftriaxone 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.