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With the emerging problem of antimicrobial resistance, the world is facing a slow but dangerous pandemic. While the discovery of novel antibiotics is reaching a nearly exhaustive end, new concepts for anti‐infective drugs are emerging. So‐called pathoblockers aim to de‐weaponize bacteria rather than just killing them. As the target of these molecules is typically located intracellularly, however, hitherto almost unnoticed biological barriers are emerging such as the biofilm matrix, the bacterial cell envelope, efflux pumps, and eventual bacterial metabolism. This leads to a new paradigm that is to maximize bacterial bioavailability. To overcome the bacterial barriers, especially when further optimization of the active molecules is not possible, functional materials are needed to engineer innovative delivery systems. Those may not only enable novel anti‐infective molecules to reach their targets, but will also improve the bacterial bioavailability of existing anti‐infectives. Additionally, there is a need for better infection models that allow studying drug effects on both the bacteria and the host in a relevant manner as needed for rational anti‐infective drug development. [ABSTRACT FROM AUTHOR]