The treatment of wound infection still constitutes a major threat in health care due to the increasing number of bacterial resistances and the difficulty of timely infection detection. Here, we present a smart antimicrobial system that is activated in case of infection based on elevated lysozyme activities. N-acetyl chitosan (degree of N-acetylation: 40%) was synthesized and hydrolysis by lysozyme in artificial wound fluid (AWF) was demonstrated. This resulted in the formation of N-acetylated chito oligosaccharides (COS) with a degree of polymerization of 2-5 units. The COS were shown to serve as substrate for cellobiose dehydrogenase (CDH) leading to the production of 1mM antimicrobial hydrogen peroxide (H2O2) after 24h incubation at 37 degrees C in AWF. Growth inhibition was seen upon incubation of Escherichia coli and Staphylococcus aureus with this chitosan-CDH system over 8h. This approach represents the first self-regulating system for the infection responsive inhibition of bacterial growth in response to lysozyme as infection biomarker. Biotechnol. Bioeng. 2017;114: 416-422. (c) 2016 Wiley Periodicals, Inc.