The remarkable ability of bacteria to develop resistance to antibacterial agents drives the continued need for new antibacterial targets and novel antimicrobial agents. Despite bacterial threats to public health, only five major pharmaceutical companies currently have active antibacterial drug discovery programs, and the target-based high-throughput screening (HTS) approach has had limited success in this field—largely because known antibacterial drugs occupy a unique physicochemical property space distinct from other therapeutic areas, while corporate compound libraries are biased toward compounds with oral bioavailability. However, Pfizer’s study showed that repurposing external compound libraries (originally for eukaryotic protein kinases) identified pyridopyrimidines active against Gram-negative bacteria by targeting the ATP-binding site of bacterial biotin carboxylase (BC), demonstrating the feasibility of finding ATP-competitive antibacterials with good selectivity and indicating the ATP-binding site of bacterial enzymes as a promising target. Bacterial genomes encode hundreds of ATP-binding proteins (e.g., DNA gyrase), but targeting their ATP-binding sites was once taboo due to high intracellular ATP concentrations (0.6–18 mM); yet the success of human ATP-competitive protein kinase inhibitors suggests this is not an absolute obstacle. Selectivity relies on dissimilarities in ATP-binding domains between bacterial and eukaryotic enzymes—though some domains are structurally superimposable despite low sequence homology, strategies like structure-based design targeting adjacent hydrophobic pockets can achieve selectivity. This Perspective discusses approaches to discover ATP-competitive inhibitors (e.g., natural products like novobiocin targeting DNA gyrase GyrB) and addresses selectivity challenges, using enzymes with available structural data (e.g., DNA gyrase, topoisomerase IV, biotin carboxylase) to illustrate the potential of bacterial ATP-binding sites as drug targets.