Malabika Sarker, Sidharth Chopra, Kristien Mortelmans, Krishna Kodukula, Carolyn Talcott and Amit K. Galande
Antibiotic discovery aimed at conventional targets such as proteins and nucleic acids faces challenges from mutations and antibiotic resistance. Small molecule metabolites, however, can be considered resistant to change, as they do not undergo rapid mutations. Developing analogs or scavengers of essential microbial metabolites as antibiotics is a promising strategy that can delay drug resistance. The objective of this work was to identify microbial metabolites that are most suitable targets for antimicrobial discovery. We performed extensive literature mining and systems level pathway analysis to identify bacterial metabolites that fulfill the criteria for drug targets. The BioCyc interactive metabolic pathway maps and Pathway Tools software were used to corroborate our finding. We identified ten metabolites as potential candidates for developing novel antibiotics. These metabolites are Lipid II, meso-diaminopimelate, pantothenate, shikimate, biotin, L-aspartyl-4-phosphate, dTDP-?-L-rhamnose, UDP-Dgalacto- 1,4-furanose, des-N-acetyl mycothiol, and Siroheme. The article describes the selection criteria, analysis of metabolic pathways, and the potential role of each of the ten metabolites in therapeutic intervention as broadspectrum antibiotics with emphasis on M. tuberculosis. Our study revealed previously unexplored targets along with metabolites that are well established in antibiotic discovery. Identification of established metabolites strengthen our analyses while the newly discovered metabolites could lead to novel antimicrobials.
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