Bioprocess strategies for intensification of microbial validamycin A production

Validamycin A is an extensively used biopesticide, a trehalase inhibitor used to control various plant pathogens, such as Rhizoctonia solani. This potent molecule exhibits low plant toxicity and high efficacy against crop diseases, including sheath blight of rice, bottom rot on lettuce, and black scurf on potatoes. The large-scale application of this secondary metabolite produced by Streptomyces hygroscopicus has led to extensive research on its microbial production strategies. These include strain improvement through metabolic engineering, optimization of fermentation media and fermentation mode, and induced expression through stress signals. This review begins with detailed description of metabolic pathway for the production of validamycin A, which is critical for any production process development. This study includes an analysis of various strategies for enhancing the production of validamycin A. The effects of stress conditions, such as high alkalinity or pH, temperature shock, and supplementation of microbial agents, have been evaluated to determine their impact on secondary metabolites in general and validamycin A specifically. This opens a new avenue for applying controlled stress for secondary metabolism enhancement to achieve a high product yield. This report also encompasses bottlenecks and future perspectives on validamycin A production. It forecasts the future of validamycin A bioprocessing by the integration of advanced technologies such as Process Analytical Techniques (PAT), metabolomics by Multivariate Data Analysis (MVDA), and co-culture fermentation systems. The novelty of this report lies in the fact that limited literature is available that compiles bioprocess strategies for the production of this potent, commercially viable compound. The strategies discussed in this review can be evaluated and applied for production of other secondary metabolites by microbial systems.