Prevention and Restriction of Antimicrobial Resistance in Pneumococci by Multi-Level Modelling

肺炎链球菌是工业化国家和发展中国家的主要健康威胁。这种病原体既影响年轻人，也影响老年人，既影响免疫能力强的人，也影响免疫功能低下的人。通过不同种群内的基因重组，单个菌株不仅能够逃避疫苗接种，而且能够获得抗微生物药物耐药性（AMR），然后可以传播。本研究旨在了解该肺炎球菌抗菌素耐药性在遗传、细菌、宿主和种群水平上的机制和分布，为抗菌素耐药性的风险评估、预防和减少制定新的策略。特别是，环境、免疫和药理学驱动的抗性出现和选择，遗传群体动态，以及新性状在不同寄主条件下的适应性将被分析和建模。为此目的，成立了一个由具有互补专门知识的研究人员组成的多国财团。该联盟可以获得临床重要的新出现的肺炎球菌AMR菌株，以及来自临床队列的相关患者元数据（临床、遗传和转录组学），以及来自泰国队列的非常详细的携带样本。联盟成员在微生物学、细菌遗传学、生物信息学、体内/体外模型方面具有成熟的专业知识，而其他成员则是儿科和成人肺炎球菌感染治疗方面的临床专家。在共同努力下，该联盟将通过在不同环境中对抗菌素耐药性的出现、选择和传播进行多层次建模，制定针对主要健康威胁的抗菌素耐药性对策。

Streptococcus pneumoniae is a major health threat in industrialized and developing countries. The pathogen affects both young and old people, immune-competent as well as immunocompromised individuals. By genetic recombination within diverse populations, individual strains are not only able to evade vaccination but also able to acquire antimicrobial resistance (AMR), which can then be transmitted onwards.This proposal aims to understand the mechanisms and distribution of this pneumococcal AMR repertoire at the genetic, bacterial, host and population levels to layout new strategies for risk assessment, prevention and reduction of AMR. In particular, the environmental, immunological and pharmacological drivers of resistance emergence and selection, the genetic population dynamics, as well as the fitness of the new traits in different host conditions will be analysed and modelled.To this end, a multinational consortium of researchers with complementary expertise has been formed. Available to the consortium are clinically important and newly emerged pneumococcal AMR strains, together with related patient metadata (clinical, genetic and transcriptomic) from clinical cohorts as well as highly detailed carriage sampling from a Thai cohort. Consortium members have proven expertise in microbiology, bacterial genetics, bioinformatics, in vivo/in vitro models while others are clinicians expert in the treatment of pneumococcal infections in both paediatric and adult patients.In a concerted effort, this consortium will develop countermeasures against antimicrobial resistance in a major health threat by multi-level modelling of its resistance emergence, selection, and transmission in diverse environments.