Application of Acid and Cold Stresses to Enhance the Production of Clavulanic Acid by Streptomyces clavuligerus

  • K. C. S. Rodrigues
  • C. L. L. Costa
  • A. C. Badino
  • D. B. Pedrolli
  • J. F. B. Pereira
  • M. O. CerriEmail author


Clavulanic acid (CA) is frequently prescribed for treatment of bacterial infections. Despite the large number of studies concerning CA production, there is still a need to search for more effective and productive processes because it is mainly produced by biochemical route and is chemically unstable. This paper evaluates the influence of acid and cold stresses on CA production by Streptomyces clavuligerus in bench scale stirred tank bioreactor. Four batch cultures were conducted at constant pH (6.8 or 6.3) and temperature (30, 25, or 20 °C) and five batch cultures were performed with application of acid stress (pH reduction from 6.8 to 6.3), cold stress (reduction from 30 to 20 °C), or both. The highest maximum CA concentration (684.4 mg L−1) was obtained in the culture conducted at constant temperature of 20 °C. However, the culture under acid stress, in which the pH was reduced from 6.8 to 6.3 at a rate of 0.1 pH unit every 6 h, provided the most promising result, exhibiting a global yield coefficient of CA relative to cell formation (YCA/X) of 851.1 mgCA gX−1. High YCA/X values indicate that a small number of cells are able to produce a large amount of antibiotic with formation of smaller amounts of side byproducts. This could be especially attractive for decreasing the complexity and cost of the downstream processing, enhancing CA production.


Clavulanic acid Streptomyces clavuligerus Process enhancing Stress induction Cold stress Acid stress Batch fermentation 


Funding Information

The authors would like to thank Coordination for the Improvement of Higher Education Personnel (CAPES, process AUXPE 1363/2015) and the National Council for Scientific and Technological Development (CNPq, process #471848/2013-1) for financial support of this work. J. F. B. Pereira acknowledges the support of FAPESP (grant #2014/16424-7).

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflicts of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Graduate Program of Chemical EngineeringFederal University of São CarlosSão CarlosBrazil
  2. 2.Department of Bioprocesses and Biotechnology, School of Pharmaceutical SciencesSão Paulo State University – UNESPAraraquaraBrazil

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