Production of clavulanic acid by Streptomyces clavuligerus in batch cultures without and with glycerol pulses under different temperature conditions

Clavulanic acid (CA) is a potent beta-lactamase inhibitor produced by Streptomyces clavuligerus. Like other beta-lactam compounds, CA is chemically unstable at high temperatures. The decomposition of CA during bacterial fermentation reduces its concentration in the broth, resulting in low yields. This study investigated the use of temperature reduction to obtain high CA production during fermentation employing cultures of S. clavuligerus. Simple batch cultures, and batch cultures with glycerol pulses, were performed at different temperatures in shake flasks at 250 rpm, and pH 6.8. Firstly, three batch cultures using glycerol as carbon source were carried out at temperatures of 30 (control), 25, and 20 °C. Next, three batch cultures were carried out with temperature reductions from 30 to 25 °C, 30 to 20 °C, and 25 to 20 °C, after glycerol exhaustion. CA production generally increased in cultures with temperature reduction and glycerol feeding. Maximum CA concentration of 1534.3 mg L−1 was achieved in a culture maintained at a constant temperature of 20 °C, with one pulse of glycerol. Under these conditions, both glycerol uptake rate and CA degradation were low. The results obtained demonstrate the potential of temperature reduction in the optimization of CA production by S. clavuligerus.

► Improvement of the clavulanic acid production.
► Batch cultures with glycerol pulses at low temperature.
► Clavulanic acid production rate and clavulanic acid degradation rate as function of the temperature.