AIM: Photodynamic inactivation of microbes can efficiently eradicate antibiotic-resistant strains. Systematic structural modification was used to investigate how porphyrin-based photosensitizers (PSs) could be designed for improved antibacterial activity. MATERIALS & METHODS: Zinc(II)5,10,15,20-tetrakis(N-alkylpyridinium-2(3,4)-yl)porphyrins presenting systematic modifications at the periphery of the porphyrin ring were evaluated for toxicity and antimicrobial photodynamic activity by measuring metabolic activity, cell membrane integrity and viability using antibiotic-sensitive and resistant Escherichia coli strains as model Gram-negative targets. RESULTS: Maximal sensitizer uptake, and, upon illumination, decrease of viable bacteria by >6 log10 were achieved by positively charged amphiphilic PSs with longer (six to eight carbon) alkyl substituents. CONCLUSION: Antibacterial photoefficiency (throughout the text photoefficiency has been used as equivalent of photocytotoxic efficacy) can be increased by orders of magnitude by increasing the lipophilicity of cationic alkylmetalloporphyrin PSs.