biostudies-literaturePereira FNIAID NIH HHSNIH HHS63-76https://www.ebi.ac.uk/biostudies/studies/S-EPMC11908387biostudies-literatureUnknown88Plecomacrolides, such as concanamycins and bafilomycins, are potent and specific inhibitors of vacuolar-type ATPase. Concanamycins are 18-membered macrolides with promising therapeutic potential against multiple diseases, including viral infection, osteoporosis, and cancer. Due to the complexity of their total synthesis, the production of concanamycins is only achieved through microbial fermentation. However, the low titers of concanamycin A and its analogs in the native producing strains are a significant bottleneck for scale-up, robust structure-activity relationship studies, and drug development. To address this challenge, we designed a library of engineered Streptomyces strains for the overproduction of concanamycin A-C by combining the overexpression of target regulatory genes with thMetabolic engineeringOptimized production of concanamycins using a rational metabolic engineering strategy.PMC11908387R01 AI148383S10 OD021619Pereira FHarte RJLev KCondren ARGalvez JVerhey-Henke LMcCauley MSherman DHfalseOptimized production of concanamycins using a rational metabolic engineering strategy.Plecomacrolides, such as concanamycins and bafilomycins, are potent and specific inhibitors of vacuolar-type ATPase. Concanamycins are 18-membered macrolides with promising therapeutic potential against multiple diseases, including viral infection, osteoporosis, and cancer. Due to the complexity of their total synthesis, the production of concanamycins is only achieved through microbial fermentation. However, the low titers of concanamycin A and its analogs in the native producing strains are a significant bottleneck for scale-up, robust structure-activity relationship studies, and drug development. To address this challenge, we designed a library of engineered Streptomyces strains for the overproduction of concanamycin A-C by combining the overexpression of target regulatory genes with th2025-01-01T00:00:00Z2025 Mar2026-06-01T19:02:53.34Z2025-04-04T03:02:15.339ZS-EPMC119083873958134210.1016/j.ymben.2024.11.008