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。该病原体影响年轻人和老年人、免疫能力强的人和免疫功能低下的人。通过不同群体内的基因重组，个体菌株不仅能够逃避疫苗接种，而且能够获得抗菌素耐药性（AMR），然后继续传播。本提案旨在了解这种肺炎球菌AMR库在遗传、细菌、宿主和人群水平上的机制和分布，为风险评估、预防和减少AMR制定新策略。特别是，将对耐药性出现和选择的环境、免疫学和药理学驱动因素、遗传群体动态以及新性状在不同宿主条件下的适应性进行分析和建模。 为此，一个具有互补专业知识的跨国研究人员联盟已经成立。该联盟可获得临床上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）以及来自泰国队列的高度详细的携带样本。联盟成员在微生物学、细菌遗传学、生物信息学、体内/体外模型方面拥有经过验证的专业知识，而其他成员则是治疗儿童和成人肺炎球菌感染的临床医生。在共同努力下，该联盟将通过对不同环境中耐药性出现、选择和传播的多层次建模，制定针对主要健康威胁的抗菌药物耐药性的对策。

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.