Cultivation Conditions and Optimization Strategies for Antibiotic-Producing Microorganisms: Focus on Actinomycetes

Antibiotics remain indispensable for treating bacterial infections, yet accelerating antimicrobial resistance is reducing their clinical effectiveness and increasing the demand for reliable, high-yield production. Because most major antibiotics originate from microbial secondary metabolism, understanding and controlling cultivation conditions is essential for both laboratory reproducibility and industrial-scale fermentation. This review analyzes cultivation and process factors that determine antibiotic productivity in antibiotic-producing microorganisms, with emphasis on actinomycetes (especially Streptomyces). The findings highlight how undefined (complex) media can support growth but reduce comparability, whereas defined media improve control and interpretation of physiological responses. Carbon and nitrogen sources strongly shape pathway activation through catabolite and nitrogen regulation, while pH and temperature influence morphology, enzyme activity, and the timing of entry into idiophase. Evidence also supports roles for lipid and fatty-acid components in selected systems, as well as precursor feeding strategies and feedback inhibition (retroinhibition) that can either enhance or suppress biosynthesis depending on pathway control. Inoculum age, mycelial state, aeration/hydrodynamics, and typical fermentation durations (often multi-day) further determine yield stability. Optimizing these upstream variables can improve productivity and batch-to-batch reproducibility and supports future research integrating omics-guided optimization and metabolic engineering.