Nutritional Stress Leads to Persistence and Persister-like Growth in Staphylococcus aureus

<i>Staphylococcus aureus</i> is a versatile zoonotic pathogen capable of causing a wide range of infections. Due to the organism's ability to persist, recalcitrant and recurring infections are a major concern for public and animal health. This study investigated the establishment of persistence using two <i>S. aureus</i> strains-ATCC 29740, a bovine mastitis isolate, and USA300, a human clinical isolate-under substrate depletion. This nutritional stress established a persistence phenotype where the strains remained persistent for >120 days at notable concentrations [>2 log10 CFU/mL] and developed persister-like growth, including small colony variant formations. With RT-qPCR, we found the cell density was higher than represented by the plate count while the intracellular ATP remained constant during the persistence phase. These findings indicate that <i>S. aureus</i> has complex survival strategies to support its persistent state, providing a host-specific perspective when addressing recurrent infections in human and animal infectious diseases.