Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins. (21st July 2020) - Gulati, Sunita
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. Abstract : Gonococci use host-derived sialic acid to evade immune defenses. Intravaginal administration of sialic acid analogs (nonulosonates) renders gonococci susceptible to host immunity and accelerates their clearance in mice. We show that cathelicidins are required for efficacy of nonulosonates in vivo.