Bacterial P450 engineering for production of high value antibacterials

BBSRC：Sian Thistlethwaite：BB/M011208/1许多药物是通过传统的有机途径合成的，但是这种方法可能是费力和昂贵的，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路线发展，以开发可持续的、更便宜的商业生产路线。这对于抗菌剂的发现至关重要，因为需要替代方法来解决抗菌剂耐药性危机。P450 BM 3由于其快速催化，多种生物转化和变体混杂性而经常被利用，从而产生有价值的现有和新的代谢产物。我们的目标是通过筛选Munro组开发的BM 3变体来解决抗菌药物耐药性问题，以对抗Auclair组开发的抗菌和细菌调节泛酸酰胺类似物。将针对几种细菌菌株筛选新的类似物，以评估其抗菌/细菌调节活性。利用生物合成产生一类化合物的新类似物，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，这可能会产生几种具有新的抗菌作用模式的感兴趣的类似物。

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.