Bacterial P450 engineering for production of high value antibacterials

许多药物都是通过传统的有机路线合成的，然而这种方法既费力又昂贵，而且有许多困难的合成步骤。药物合成正朝着生物合成等替代合成途径发展，以开发可持续的、更便宜的商业生产途径。这对抗菌药物的发现至关重要，因为需要其他方法来解决抗菌药物耐药性危机。P450 BM3由于其快速的催化作用、多样化的生物转化范围和产生有价值的现有和新的代谢物的多样性而经常被利用。我们的目标是通过筛选Munro组开发的针对Auclair组开发的抗菌和细菌调节泛酸酰胺类似物的BM3变体来解决抗菌耐药性问题。新的类似物将对几种细菌菌株进行筛选，以评估其抗菌/细菌调节活性。利用生物合成来生产一类化合物的新型类似物，这些化合物可能会使宿主免疫系统对感染性细菌重新敏感，从而产生几种具有新模式抗菌作用的感兴趣的类似物。

BBSRC : Sian Thistlethwaite : BB/M011208/1Many pharmaceutical drugs are synthesised by traditional organic routes, however this approach can be laborious and expensive with many difficult synthesis steps. Pharmaceutical synthesis is moving towards alternative synthetic routes such as biosynthesis in order to develop sustainable, cheaper routes of commercial production. This is crucial for antibacterial discovery, as alternative approaches are required to tackle the antibacterial resistance crisis. P450 BM3 is often utilised due to its rapid catalysis, diverse range of biotransformations and variant promiscuity yielding valuable existing and novel metabolites. We aim to address the problem of antibacterial resistance by screening variants of BM3 developed in the Munro group against antibacterial and bacterio-modulating pantothenamide analogs developed in the Auclair group. New analogs will be screened against several bacterial strains to assess their antibacterial/bacterio-modulating activity. Utilising biosynthesis to produce novel analogs of a class of compounds that will potentially resensitize the host immune system to infectious bacteria may yield several analogs of interest with a new mode of antibacterial action.