SMALL MOLECULE INHIBITORS OF CARIOGENIC BIOFILMS

描述（申请人提供）：龋齿（蛀牙）是困扰美国公众的最普遍的传染病。生物膜的形成对致龋细菌变形链球菌引起的龋齿的发病至关重要。变形链球菌已经适应了生物膜的生活方式。生物膜内的细菌对传统抗生素的耐药性极高（100-1000倍）；因此，开发能够抑制变形链球菌形成生物膜的新型抗生物膜试剂是治疗和预防龋齿的必要和关键。最有效和最通用的一类具有抗生物膜特性的分子是由Melander小组从天然海洋产品中发现的2-氨基咪唑（2-AI）支架衍生的分子。2-AI衍生物能够抑制和分散革兰氏阴性和革兰氏阳性细菌形成的多种生物膜。鉴于这种2-AI衍生物的成功，我们已经开始对设计、筛选和表征其衍生物感兴趣，这些衍生物将抑制和分散变形链球菌的生物膜，同时警告小分子化合物不会影响共生链球菌的生物膜形成。我们将使用血链球菌和戈登链球菌作为模型共生链球菌，因为它们都是牙齿表面的主要定植菌，在健康的口腔中数量占主导地位。我们的初步研究表明，对2-AI进行修饰可以提高2-AI衍生物的选择性，并且我们已经获得了对S. mutans具有中等选择性的2-AI类似物。我们目前的目标是开发新的基于小分子的疗法。我们假设2-AI衍生物可以作为支架来设计高级类似物，这些类似物具有更高的选择性和抑制变形链球菌的效力。具体目标1：合成和筛选多种2-AI衍生物文库，以鉴定具有选择性抗肿瘤生物膜活性的化合物。具体目的2：确定小分子铅在龋动物模型中的作用。特异性目标3：鉴定和表征强效小分子的分子靶标，确定抗致癌生物膜活性的潜在机制。为了实现研究目标，已经建立了一个由化学家、动物模型专家、微生物学家和牙医科学家组成的多学科研究团队。与开发2-AI衍生物的抗生物膜合成化学先驱Christian Melander博士、龋齿研究的领导者Sue Michalek博士和牙医科学家Noel Childers博士的密切合作将促进新的抗致癌生物膜化合物的开发。这项研究将对公众的口腔健康产生直接影响，因为活性化合物可以很容易地发展成一种有效的治疗方法，可以被公众日常使用。

DESCRIPTION (provided by applicant): Dental caries (tooth decay) is the most prevalent infectious disease afflicting American Public. Biofilm formation is crucial for the pathogenesis of dental caries caused by cariogenic bacterium Streptococcus mutans. S. mutans has adapted to the biofilm lifestyle. Bacteria within a biofilm are extremely (100-1000 fold more) resistant to traditional antibiotics; therefore development of new classes of anti-biofilm reagents with the ability to inhibit biofilm formation by S. mutans is necessary and critical for the treatment and prevention of dental caries. The most potent and versatile class of molecules with anti-biofilm properties are those derived from the 2-aminoimidazole (2-AI) scaffold discovered by the Melander group from natural marine products. The 2-AI derivative is capable of inhibiting and dispersing diverse biofilms formed by Gram-negative and Gram-positive bacteria. Given the success of this 2-AI derivative, we have become interested in designing, screening and characterizing its derivatives that will both inhibit and disperse S. mutans biofilms with the caveat that the small molecule compounds will not affect biofilm formation by commensal streptococci. We will use Streptococcus sanguinis and Streptococcus gordonii as model commensal streptococci as both are primary colonizers of the tooth surface and numerically dominated in the healthy oral cavity. Our preliminary studies have shown that modification of 2-AI can enhance selectivity of the 2-AI derivatives, and we have derived a 2-AI analogue that exhibits moderate selectivity towards inhibiting S. mutans. The goal of our current proposal is to develop new small molecule-based therapeutics. We hypothesize that 2-AI derivative can be used as a scaffold to design advanced analogues that: are more selective and potent towards inhibiting S. mutans. Three specific aims are proposed to achieve the goal: Specific Aim 1: Synthesize and screen diverse libraries of 2-AI derivatives to identify compounds with selective anticariogenic biofilm activity. Specific Aim 2: Determine efficacy of the lead small molecules in an animal model of dental caries. Specific Aim 3: Identify and characterize molecular targets of the potent small molecules and determine the underlying mechanism of the anticariogenic biofilm activity. A multidisciplinary research team among chemists, animal model experts, microbiologists and dentist scientists has been established to achieve the research goal. The close collaboration with Dr. Christian Melander, a pioneer in anti-biofilm synthetic chemistry to develop 2-AI derivatives, Dr. Sue Michalek, a leader in the caries research, and Dr. Noel Childers, a dentist scientist will facilitate the development of new anticariogenic biofilm compounds. This study will have a direct impact on the oral health of the public since the active compounds can be readily developed into an effective therapy that can be used routinely by the public.