NovaBiotics Ltd, Aberdeen, United Kingdom.
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Front Cell Infect Microbiol. 2021 Sep 22;11:718213. doi: 10.3389/fcimb.2021.718213. eCollection 2021.
is a major opportunistic human pathogen which employs a myriad of virulence factors. In people with cystic fibrosis (CF) frequently colonises the lungs and becomes a chronic infection that evolves to become less virulent over time, but often adapts to favour persistence in the host with alginate-producing mucoid, slow-growing, and antibiotic resistant phenotypes emerging. Cysteamine is an endogenous aminothiol which has been shown to prevent biofilm formation, reduce phenazine production, and potentiate antibiotic activity against , and has been investigated in clinical trials as an adjunct therapy for pulmonary exacerbations of CF. Here we demonstrate (for the first time in a prokaryote) that cysteamine prevents glycine utilisation by in common with previously reported activity blocking the glycine cleavage system in human cells. Despite the clear inhibition of glycine metabolism, cysteamine also inhibits hydrogen cyanide (HCN) production by , suggesting a direct interference in the regulation of virulence factor synthesis. Cysteamine impaired chemotaxis, lowered pyocyanin, pyoverdine and exopolysaccharide production, and reduced the toxicity of secreted factors in a infection model. Thus, cysteamine has additional potent anti-virulence properties targeting , further supporting its therapeutic potential in CF and other infections.
铜绿假单胞菌是一种主要的机会性病原体，它利用多种毒力因子。在囊性纤维化 (CF) 患者中，铜绿假单胞菌经常定植于肺部，并发展为慢性感染，随着时间的推移毒力逐渐降低，但往往会适应宿主，产生产生藻酸盐的粘液型、生长缓慢、对抗生素耐药的表型以利于持续存在。半胱胺是一种内源性的氨硫醇，已被证明可预防生物膜形成、减少吩嗪的产生，并增强抗生素对铜绿假单胞菌的活性，已在临床试验中作为 CF 肺部感染加重的辅助治疗进行了研究。在这里，我们首次在原核生物中证明，半胱胺可阻止铜绿假单胞菌利用甘氨酸，与先前报道的阻断人细胞中甘氨酸裂解系统的活性一致。尽管明显抑制了甘氨酸代谢，但半胱胺也抑制了铜绿假单胞菌产生氢氰酸 (HCN)，表明其直接干扰了毒力因子合成的调节。半胱胺可损害铜绿假单胞菌的趋化性，降低绿脓菌素、吡咯并喹啉醌和胞外多糖的产生，并降低感染模型中铜绿假单胞菌分泌因子的毒性。因此，半胱胺具有针对铜绿假单胞菌的额外的强效抗毒力特性，进一步支持其在 CF 和其他感染中的治疗潜力。
