Systematic analysis of microorganisms’ metabolism for selective targeting

Selective drug targets (i.e., narrow-spectrum antibiotics) can minimize side effects of antibiotic treatments compared to broad-spectrum antibiotics due to their specific targeting of the organisms responsible for the infection. Furthermore, combating an infectious pathogen, especially a drug-resistant organism, is more efficient by attacking multiple targets. Here, we combined synthetic lethality with selective drug targeting to obtain multi-target and organism-specific potential drug candidates by systematically analyzing the genome-scale metabolic models of six different microorganisms. By considering microorganisms as targeted or conserved in one- to six-member groups, we designed 665 individual case studies. For each case, we identified single essential reactions as well as double, triple, and quadruple synthetic lethal reaction sets that are lethal for targeted microorganisms and neutral for conserved ones. As expected, the number of obtained solutions for each case depends on the genomic similarity between the studied microorganisms. Mapping the identified potential drug targets to their corresponding pathways showed the importance of key subsystems such as cell envelope biosynthesis, glycerophospholipid metabolism, membrane lipid metabolism, and the nucleotide salvage pathway. To assist validation and further investigation of our proposed potential drug targets, we introduced two sets of targets that can potentially address a substantial portion of the 665 cases. We expect that the obtained solutions provide helpful insights into designing narrow-spectrum drugs that selectively cause system-wide damage only to the target microorganisms.