Anticipating antimicrobial resistance: predicting the resistance-spectrum of emerging lactamase variants using atomistic simulation and experiment

预测抗菌药物耐药性：使用原子模拟和实验预测新兴内酰胺酶变体的耐药谱

• 批准号: 2767481
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2767481
• 关键词: Anticipating; antimicrobial; resistance; predicting; spectrum

Rising antibiotic resistance is a major problem for human health. Resistance to lactams, the single most important antibiotic class, usually arises through their breakdown by lactamases (BLs). Many BL producing bacteria are multi-drug resistant and may cause untreatable infections. Worryingly, new BL variants conferring resistance are detected frequently. As bacteria usually harbour multiple BLs, it is often not clear which BLs cause resistance against which lactam antibiotics, and, importantly, how. Using multi-scale computer simulations, we have previously calculated the efficiency of lactam acyl-enzyme formation and breakdown for a number of known BLs, thereby predicting whether and how they confer resistance to specific lactams. Genomic analysis of clinical isolates as well as lab experiments can identify new BL variants and thereby provide insights into the evolution of BLs with enhanced antibiotic breakdown activity. In this atomistic simulation-led multidisciplinary project, the main aim will be to understand increased activity of newly arising BLs against key lactam antibiotics (e.g. cephalosporins, carbapenems), and then predict potential new variants. Computational assays based on multi-scale simulations will be used to assess formation and breakdown of the acyl-enzymes of 1) recently discovered, clinically relevant serine BLs; and 2) serine BLs with increased resistance obtained in the lab (e.g. by our international collaborators). This is challenging, as exact structures of these variants (in complex with antibiotics) are often not available and different reaction mechanisms will need to be explored. Notably, we will use the insights gained and protocols developed to predict new putative resistance-conferring BL variants from computational screening of mutations at key positions. Computational predictions of antibiotic breakdown by selected BLs and variants will then be validated by experimental determination of lactam hydrolysis.

抗生素耐药性上升是人类健康的主要问题。对乳糖的耐药性是最重要的抗生素类别，通常是由于其乳糖酶（BLS）的分解而产生的。许多BL产生的细菌具有多药耐药性，可能引起不可治疗的感染。令人担忧的是，经常检测到新的BL变体。由于细菌通常具有多个BLS，因此尚不清楚哪些BL会引起乳糖抗生素的抗性，而且重要的是如何。使用多尺度的计算机模拟，我们先前已经计算了许多已知BLS的LACTAM酰基 - 酶形成和分解的效率，从而预测了它们是否以及如何赋予对特定lactams的抗性。临床分离株以及实验室实验的基因组分析可以鉴定新的BL变体，从而提供有关BLS演变的见解，并具有增强的抗生素分解活性。在这个由原子模拟主导的多学科项目中，主要目的是了解新出现的BLS的活动增加，对lactam lactam抗生素（例如头孢菌素，碳青霉烯），然后预测潜在的新变体。基于多尺度模拟的计算分析将用于评估1）最近发现的临床相关丝氨酸BLS的酰基酶的形成和分解； 2）在实验室中获得的阻力增加（例如，由我们的国际合作者）。这是具有挑战性的，因为这些变体的确切结构（与抗生素复杂）通常不可用，需要探索不同的反应机制。值得注意的是，我们将利用获得的见解，并开发了协议来预测关键位置突变的计算筛选的新推定抗性限制BL变体。然后，将通过实验测定乳糖水解对抗生素分解的计算预测将得到验证。