An efficient treatment of infections using antimicrobial photodynamic therapy (aPDT) anticipates that uptake of photosensitizer (PS) by bacterial cells is very fast and effective. In this work, the design, synthesis, characterization, and photodynamic activity of amphiphilic, water-soluble zinc(ii)phthalocyanine (Zn(ii)Pc) molecules bearing none, three or six thiophenyl moieties are described. We show that PSs that contain no or flexible substituents on non-peripheral positions can photoinactivate microbes at very low loading concentrations and low light doses. In contrast, a PS derivative that contains non-flexible substituents is rendered less effective, despite an increased generation of cytotoxic singlet oxygen, higher lipophilicity and a lower tendency to aggregate. Our unexpected finding emphasizes the role of the morphology of PSs in bacterial cell-molecule interactions and suggests another relevant and hitherto disregarded characteristic to improve PS design.