Systematic analysis of microorganisms' metabolism for selective targeting.

Selective drugs with a relatively narrow spectrum can reduce the side effects of treatments compared to broad-spectrum antibiotics by specifically targeting the pathogens responsible for infection. Furthermore, combating an infectious pathogen, especially a drug-resistant microorganism, is more efficient by attacking multiple targets. Here, we combined synthetic lethality with selective drug targeting to identify 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 groups ranging from one to six members, 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 highlighted the importance of key subsystems such as cell envelope biosynthesis, glycerophospholipid metabolism, membrane lipid metabolism, and the nucleotide salvage pathway. To assist in the validation and further investigation of our proposed potential drug targets, we introduced two sets of targets that can theoretically address a substantial portion of the 665 cases. We expect that the obtained solutions provide valuable insights into designing narrow-spectrum drugs that selectively cause system-wide damage only to the target microorganisms.