Advancements in biotechnology over the past few decades have enabled scientists to discover a wide range of novel microbial compounds with therapeutic potential. High-throughput screening of microorganisms isolated from diverse environments has led to the identification of many microbial metabolites exhibiting antimicrobial, antifungal and anticancer activities. For example, screening of actinomycetes isolated from soil samples collected in Borneo yielded the antibiotic teixobactin which showed potent activity against drug-resistant pathogens. Large culture collections maintained by research institutions also continue to be a rich source for natural product discovery. Systematic exploration of these cultured microbes has resulted in the development of several clinically useful microbial APIs such as daptomycin and micafungin.

Biosynthetic Gene Clusters and Metabolic Engineering

Identification of the biosynthetic gene clusters responsible for microbial API production has opened new avenues for enhancing API yields through metabolic engineering approaches. Advances in whole genome sequencing and bioinformatics tools have enabled rapid characterization of biosynthetic gene clusters. Genes involved in API biosynthesis can be expressed heterologously in engineered microbial production hosts with optimized fermentation conditions. Metabolic engineering strategies such as gene overexpression, gene knockout and feedback regulation alterations have been employed to increase Microbial API titers. For example, combinatorial biosynthesis of non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) genes led to generation of novel hybrid antimicrobial compounds.

Fermentation Process Development

Establishing an efficient large-scale fermentation process is crucial for the commercial production of microbial APIs. Conventionally, batch and fed-batch fermentations are carried out in stirred-tank bioreactors for API production. However, recent years have seen a shift towards continuous fermentation approaches using cell recycling bioreactors to enhance volumetric productivity. Process parameters such as culture media composition, aeration, agitation rate and pH/temperature controllers need to be tightly controlled. Post-fermentation steps involve cell separation, product recovery from broth and purification. Continuous product monitoring and quality control testing as per regulatory guidelines are also important. Application of process analytical technologies facilitates process optimization, scale-up and quality assurance.