Cooperation and cheating in the evolution of antibiotic resistance in bacteria

细菌抗生素耐药性进化中的合作与欺骗

• 批准号: 9043131
• 负责人: Jeff Gore
• 金额: $ 28.25万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043131
• 关键词: Ampicillin Resistance; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Model; Cell Density; Cell Wall; Cells; Chloramphenicol; Coculture Techniques; Cooperative Behavior; Disease; Environment; Enzymes; Escherichia coli; Evolution; Excision; Extended-spectrum β-lactamase; Flow Cytometry; Game Theory; Germ Cells; Growth; Health; Label; Lactamase; Lead; Measurement; Measures; Microbe; Minimum Inhibitory Concentration measurement; Modeling; Monobactams; Mutation; Nature; Pharmaceutical Preparations; Plasmids; Population; Population Dynamics; Public Health; Research; Resistance; Sucrose; System; Techniques; Testing; Time; War; Work; Yeasts; bacterial resistance; beta-Lactamase; data modeling; fitness; inhibitor/antagonist; insight; killings; laboratory experiment; migration; mutant; mutualism; novel; research study; resistant strain; theories; tool

DESCRIPTION (provided by applicant): The emergence of antibiotic resistance in bacteria is a persistent challenge to public health. beta-lactam antibiotics, which kill bacteria by inhibiting cell wall synthesis, are both the oldest and most widely used class of antibiotics. Bacteria can gain resistance to these antibiotics by expressing the enzyme lactamase, which inactivates the antibiotic. This inactivation of the antibiotic may be a cooperative behavior because the entire cell population benefits from the removal of the antibiotic. In this proposal we quantify the cooperative nature of bacterial growth in beta-lactam antibiotics and explore the consequences of this cooperation for the evolution of antibiotic resistance. We hypothesize that integrating modeling with quantitative measurements of the cooperative bacterial growth in antibiotics will yield novel insights into the evolution of antibiotic resistance. Preliminary experiments have characterized the manner in which bacterial populations collectively break down antibiotics in the environment. Modeling of these cooperative growth dynamics makes surprising yet testable predictions regarding which mutations in beta-lactamase will spread throughout the population. We focus on mutations in beta-lactamase that allow the enzyme to break down a wide range of clinically important drugs- such versions of the enzyme are called Extended Spectrum beta-Lactamases (ESBL) and are a serious public health concern. The approach described here is a natural extension of the PI's previous experiments studying evolutionary and population dynamics in microbes. Three specific aims will guide our study of the evolutionary dynamics of antibiotic resistance: 1) Determine how the cooperative nature of bacterial growth in beta-lactam antibiotics influences the direction of selection and the conditions that lead to the sprea of more resistant mutants. 2) Determine whether sensitive bacteria, which lack the plasmid encoding beta-lactamase, can act as "cheaters" and take advantage of the resistant bacteria that are inactivating the antibiotic. 3) Explore the conditions in which two bacterial strains, eah resistant to a single antibiotic, can cooperatively grow in a multi-drug environment. These studies present a novel set of quantitative approaches to understand the evolutionary dynamics of bacteria in the presence of antibiotics. We expect that these studies will provide new insight into the evolutionary origin of antibiotic resistance and will also help to clarify the conditions n which evolution can favor the emergence of cooperative behaviors.

描述（由申请人提供）：细菌中抗生素耐药性的出现是对公共健康的持续挑战。 β-内酰胺抗生素，通过抑制细菌来杀死细菌 细胞壁合成，都是最古老且使用最广泛的一类抗生素。细菌可以通过表达内酰胺酶来获得对这些抗生素的耐药性，从而使抗生素失活。抗生素的灭活可能是一种合作行为，因为整个细胞群都受益于抗生素的去除。在本提案中，我们量化了 β-内酰胺抗生素中细菌生长的合作性质，并探讨了这种合作对抗生素耐药性进化的影响。 我们假设，将模型与抗生素中细菌协同生长的定量测量相结合，将为抗生素耐药性的演变提供新的见解。初步实验已经描述了环境中细菌群体​​集体分解抗生素的方式。对这些合作生长动态的建模做出了令人惊讶但可测试的预测，即β-内酰胺酶的哪些突变将在整个群体中传播。我们重点关注 β-内酰胺酶的突变，这些突变使该酶能够分解多种临床上重要的药物 - 这种酶的版本被称为超广谱 β-内酰胺酶 (ESBL)，是一个严重的公共卫生问题。这里描述的方法是 PI 之前研究微生物进化和种群动态的实验的自然延伸。 三个具体目标将指导我们对抗生素耐药性进化动力学的研究：1）确定β-内酰胺抗生素中细菌生长的合作性质如何影响选择方向和导致更具耐药性突变体传播的条件。 2) 确定缺乏编码β-内酰胺酶的质粒的敏感细菌是否可以充当“作弊者”并利用使抗生素失活的耐药细菌。 3）探索两种对单一抗生素具有抗药性的细菌菌株可以在多药物环境中协同生长的条件。这些研究提出了一套新颖的定量方法来了解抗生素存在下细菌的进化动态。我们期望这些研究将为抗生素耐药性的进化起源提供新的见解，并将有助于阐明进化有利于合作行为出现的条件。