Antidiabetic "gliptins" affect biofilm formation by Streptococcus mutans
Antidiabetic "gliptins" affect biofilm formation by Streptococcus mutans
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DOI：
10.1016/j.micres.2018.02.005
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发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Vitali, Luca A.
中科院分区：
文献类型：
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作者：
De, Arpan;Pompilio, Arianna;Vitali, Luca A.
变形链球菌是一种引起龋齿的牙病原菌，它产生 X-脯氨酰二肽基肽酶（Sm-XPDAP，由 pepX 编码），这是一种已知具有营养作用的丝氨酸蛋白酶。考虑到蛋白酶作为病原体治疗靶点的潜力，本研究主要旨在研究 Sm-XPDAP 在促进毒力相关性状中的作用。二肽基肽酶 (DPP IV) 是一种在哺乳动物组织中发现的 XPDAP 类似酶，是 II 型糖尿病的众所周知的治疗靶点。基于通常用作抗人 DPP IV 药物的格列汀可能在抑制 Sm-XPDAP 后影响细菌生长的假设，我们确定了它们对变形链球菌的离体抗菌和抗生物膜活性。通过结晶紫染色确定，所有三种测试的 DPP IV 药物均减少了生物膜形成。为了将观察到的生物膜抑制与变形链球菌 UA159 中存在的人 DPP IV 类似物联系起来，生成了 pepX 同基因突变体。除了减少生物膜形成之外，对 pepX 同基因突变体形成的生物膜的 CLSM 研究表明，这些生物膜与沙格列汀存在下形成的生物膜相当，表明该酶可能在变形链球菌 UA159 的生物膜形成中发挥作用。使用 LC-MS/MS 研究了 pepX 缺失和 DPP IV 药物对蛋白质组的影响。总的来说，这项研究强调了 Sm-XPDAP 作为新型抗生物膜靶点的潜力，并提出了一种模板分子来合成有效对抗这种酶的先导化合物。
Streptococcus mutans, a dental caries causing odontopathogen, produces X-prolyl dipeptidyl peptidase (Sm-XPDAP, encoded by pepX), a serine protease known to have a nutritional role. Considering the potential of proteases as therapeutic targets in pathogens, this study was primarily aimed at investigating the role of Sm-XPDAP in contributing to virulence-related traits. Dipeptidyl peptidase (DPP IV), an XPDAP analogous enzyme found in mammalian tissues,is a well known therapeutic target in Type II diabetes. Based on the hypothesis that gliptins, commonly used as anti-human-DPP IV drugs, may affect bacterial growth upon inhibition of Sm-XPDAP, we have determined their ex vivo antimicrobial and anti-biofilm activity towards S. mutans. All three DPP IV drugs tested reduced biofilm formation as determined by crystal violet staining. To link the observed biofilm inhibition to the human-DPP IV analogue present in S. mutans UA159, a pepX isogenic mutant was generated. In addition to reduced biofilm formation, CLSM studies of the biofilm formed by the pepX isogenic mutant showed these were comparable to those formed in the presence of saxagliptin, suggesting a probable role of this enzyme in biofilm formation by S. mutans UA159. The effects of both pepX deletion and DPP IV drugs on the proteome were studied using LC-MS/MS. Overall, this study highlights the potential of Sm-XPDAP as a novel anti-biofilm target and suggests a template molecule to synthesize lead compounds effective against this enzyme.