Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins.
Gulati. Sunita S; Schoenhofen. Ian C IC; Lindhout-Djukic. Theresa T; Lewis. Lisa A LA; Moustafa. Iesha Y IY; Saha. Sudeshna S; Zheng. Bo B; Nowak. Nancy N; Rice. Peter A PA; Varki. Ajit A; Ram. Sanjay S
Key Findings
- Gonococci use host‑derived sialic acid (Neu5Ac) to resist LL‑37 and complement.
- CMP‑nonulosonate analogs (CMP‑Kdn, CMP‑Leg5,7Ac2) can be incorporated into bacterial LOS without providing resistance to LL‑37.
- Intravaginal delivery of these analogs lowered gonococcal colonization in mice, but only when cathelicidins like LL‑37 were present.
Practical Outcomes
- For now, the findings are mostly scientific and not a direct protocol you can try. They suggest that future therapies might combine LL‑37‑boosting strategies with CMP‑nonulosonate compounds to fight resistant gonorrhea, but human safety and dosing still need to be worked out.
Summary
The study shows that gonorrhea bacteria can hide from the immune system by adding a sugar called sialic acid to their surface, which makes them resistant to the natural antimicrobial peptide LL‑37. Researchers found that giving mice similar sugars (CMP‑Kdn or CMP‑Leg5,7Ac2) into the vagina keeps the bacteria vulnerable to LL‑37 and reduces infection, but this only works when LL‑37 is present. The work is still early‑stage and done in mice, so it isn’t a ready‑to‑use treatment for people yet.
Abstract
Novel therapies to counteract multidrug-resistant gonorrhea are urgently needed. A unique gonococcal immune evasion strategy involves capping of lipooligosaccharide (LOS) with sialic acid by gonococcal sialyltransferase (Lst), utilizing host-derived CMP-sialic acid (CMP-Neu5Ac in humans). LOS sialylation renders gonococci resistant to complement and cationic peptides, and down-regulates the inflammatory response by engaging siglecs. CMP-sialic acid analogs (CMP-nonulosonates [CMP-NulOs]) such as CMP-Leg5,7Ac2 and CMP-Kdn are also utilized by Lst. Incorporation of these NulO analogs into LOS maintains gonococci susceptible to complement. Intravaginal administration of CMP-Kdn or CMP-Leg5,7Ac2 attenuates gonococcal colonization of mouse vaginas. Here, we identify a key mechanism of action for the efficacy of CMP-NulOs. Surprisingly, CMP-NulOs remained effective in complement C1q-/- and C3-/- mice. LOS Neu5Ac, but not Leg5,7Ac2 or Kdn, conferred resistance to the cathelicidins LL-37 (human) and mouse cathelicidin-related antimicrobial peptide in vitro. CMP-NulOs were ineffective in Camp-/- mice, revealing that cathelicidins largely mediate the efficacy of therapeutic CMP-NulOs.
Study Information
pubmed
2020
2020-10-13T00:00:00.000Z
10.1093/infdis/jiaa438
13
53