Schulte Albert Marten, Schoenmakers Jorrit W A, van Oosten Marleen, Jutte Paul C, van Dijl Jan Maarten, Szymanski Wiktor, Feringa Ben L
Centre for Systems Chemistry, Stratingh Institute for Chemistry, Faculty for Science and Engineering, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
Department of Medicinal Chemistry, Photopharmacology and Imaging, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
ACS Cent Sci. 2025 Jun 11;11(7):1083-1093. doi: 10.1021/acscentsci.5c00437. eCollection 2025 Jul 23.
Our ability to prevent, treat, and cure bacterial infections is nowadays seriously threatened by the rise of (multidrug) antimicrobial resistance (AMR), and novel molecular approaches in the antibacterial arsenal are urgently needed. To fight the development of AMR, the field of photopharmacology aims to develop photoresponsive antimicrobials allowing for noninvasive activation of the drug only at the site needed, with spatiotemporal precision, reducing the bacterial exposure to the active antimicrobial in the environment. This study reports the development and application for the first time of a green-light-activatable variant of penicillin (), designed through the incorporation of a photocleavable protecting group. Here, we demonstrate that shows no antimicrobial activity in the dark, while it can be precisely activated through irradiation with green light. Furthermore, we show 's utility to spatially control bacterial growth, achieve light-dependent inhibition of biofilm formation, and showcase the unprecedented usage of a photoactivatable antimicrobial in a small animal infection model. Furthermore, we apply in combination with a λ-orthogonally photocaged bioactive compound to achieve photocontrol over antimicrobial activity dependent on two distinct colors of light.
如今，我们预防、治疗和治愈细菌感染的能力受到（多重）抗菌药物耐药性（AMR）上升的严重威胁，因此迫切需要抗菌武器库中的新型分子方法。为了对抗AMR的发展，光药理学领域旨在开发光响应性抗菌剂，使其仅在所需部位以时空精确性进行非侵入性激活，从而减少环境中细菌对活性抗菌剂的暴露。本研究首次报道了通过引入光可裂解保护基团设计的青霉素绿光可激活变体（）的开发和应用。在这里，我们证明在黑暗中没有抗菌活性，而通过绿光照射可以精确激活它。此外，我们展示了在空间上控制细菌生长、实现对生物膜形成的光依赖性抑制的效用，并展示了光激活抗菌剂在小动物感染模型中的前所未有的应用。此外，我们将与λ正交光笼生物活性化合物联合应用，以实现依赖于两种不同颜色光的抗菌活性的光控。
