Designing new antibiotics with a focus on gut health

抗生素的发现极大地改变了医学，但这种转变现在受到抗菌素耐药性(AMR)快速升级的威胁。AMR的传播归因于抗生素的使用和误用，造成了选择性压力，助长了医疗保健和农业中耐药细菌的增长。克服AMR的一个关键战略是对现有药物进行化学修饰，以创造具有类似活性但避免耐药的半合成类似物。然而，这些努力忽视了新药对肠道微生物群的影响，肠道微生物群是一种关键的共生细菌群落，通过定植抵抗来抵抗病原体入侵。相反，新的抗生素通常是为了对抗病原体的效力而优化的，而不是考虑对微生物群的附带影响。因此，抗生素可以不分青红皂白地抑制肠道微生物群中的有益成员以及任何病原体。我的项目旨在通过合成一个新的抗菌素库来解决这个问题，并评估它们对病原体和人类肠道微生物组的影响。在这样做的同时，我的目标是开发更多对微生物友好的药物，并寻求小分子抗生素选择性的一般规则。UKRI-BBSRC的优先领域：对抗抗菌素耐药性，综合微生物组研究

The discovery of antibiotics massively transformed medicine, but this transformation is now jeopardized by the rapid escalation of antimicrobial resistance (AMR). The spread of AMR is attributed to the use and misuse of antibiotics, creating selective pressures that fuel the growth of resistant bacteria in healthcare and agriculture. A key strategy to overcome AMR is to chemically modify existing drugs to create semi-synthetic analogues that have similar activity but evade resistance. However, these efforts have neglected the impacts of new drugs on the gut microbiome, a crucial community of commensal bacteria that resists pathogenic invasion through colonization resistance. Rather, new antibiotics are typically optimised for potency against pathogens above all else, irrespective of collateral effects on the microbiome. As a result, antibiotics can indiscriminately suppress the beneficial members of the gut microbiome alongside any pathogens. My project aims to address this problem by synthesising a library of new antibiotics and assessing their effects on both pathogens and the human gut microbiome. In doing so, I aim to both develop more microbiome friendly drugs and seek general rules underlying the selectivity of small molecule antibiotics.UKRI-BBSRC Priority Areas: Combatting antimicrobial resistance, integrative microbiome research