Lamb Evan R, Criss Alison K
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
mBio. 2025 May 14;16(5):e0014125. doi: 10.1128/mbio.00141-25. Epub 2025 Mar 31.
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 , including (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 exerts bactericidal activity against Gc and, unlike other Gram-negative bacteria, disrupts both the outer and inner membranes. C5b-C8 complex formation potentiates Gc sensitivity to azithromycin and ceftriaxone, but not lysozyme or nisin. 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 that complement manipulation can be used to combat drug-resistant gonorrhea.
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 species including (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.
补体级联反应是抵御病原体的一线防御机制。补体激活会产生膜攻击复合物（MAC），这是一种直径为10 - 11纳米的孔道，由补体蛋白C5b至C8以及聚合的C9形成。MAC嵌入革兰氏阴性菌的外膜并展现出杀菌活性。在缺乏C9的情况下，C5b - C8复合物可在膜上形成2 - 4纳米的孔道，但其与微生物控制的相关性尚不清楚。末端补体成分的缺陷会使个体特别易受包括淋病奈瑟菌（Gc）在内的致病微生物感染。淋病奈瑟菌抗生素耐药性的增加使得新的治疗策略成为当务之急。在此，我们证明人血清中的补体活性形成的MAC会破坏淋病奈瑟菌的外膜和内膜，增强抗菌药物对淋病奈瑟菌的活性，并使多重耐药的淋病奈瑟菌重新对抗生素敏感。缺乏C9的血清对淋病奈瑟菌也具有杀菌活性，并且与其他革兰氏阴性菌不同，它会破坏外膜和内膜。C5b - C8复合物的形成增强了淋病奈瑟菌对阿奇霉素和头孢曲松的敏感性，但对溶菌酶或乳链菌肽则不然。这些发现扩展了我们对补体溶解活性机制的理解，提示了末端补体介导的增强针对淋病奈瑟菌抗菌作用的大小限制，并表明补体调控可用于对抗耐药性淋病。
补体级联反应是先天性免疫系统抵御病原体的一线力量。补体激活导致革兰氏阴性菌外膜上形成膜攻击复合物（MAC）孔道，从而导致细菌死亡。无法产生MAC的个体特别易受包括淋病奈瑟菌（Gc）在内的致病微生物感染。淋病的高发病率、其诸如不孕等并发症以及对多种抗生素的高频率耐药性使得确定对抗淋病奈瑟菌的新方法变得至关重要。除了直接的抗淋病奈瑟菌活性外，我们发现MAC增强了抗生素和抗菌蛋白杀死淋病奈瑟菌的能力，并使多重耐药菌重新对抗生素敏感。最末端的成分C9是增强溶菌酶和乳链菌肽抗淋病奈瑟菌活性所必需的，但阿奇霉素和头孢曲松的活性无论有无C9都会增强。这些发现突出了MAC对淋病奈瑟菌的独特作用，并提示了对抗耐药性淋病的新的转化途径。
