When Staph aureus can't run its TCA cycle, it becomes far better at surviving both antibiotics and natural immune peptides like LL‑37, making infections harder to clear.

<i>Staphylococcus aureus</i> is widely known for its resistance and virulence causing public health concerns. However, antibiotic tolerance is also a contributor to chronic and relapsing infections. Previously, it has been demonstrated that persister formation is dependent on reduced tricarboxylic acid (TCA) cycle activity. Persisters have been extensively examined in terms of antibiotic tolerance but tolerance to antimicrobial peptides (AMPs) remains largely unexplored. AMPs are a key component of both the human and <i>Drosophila</i> innate immune response. TCA cycle mutants were tested to determine both antibiotic and AMP tolerance. Challenging with multiple classes of antibiotics led to increased persister formation (100- to 1,000-fold). Similarly, TCA mutants exhibited AMP tolerance with a 100- to 1,000-fold increase in persister formation when challenged with LL-37 or human &#x3b2;-defensin 3 (h&#x3b2;D3). The ability of TCA cycle mutants to tolerate the innate immune system was further examined with a <i>D. melanogaster</i> model. Both males and females infected with TCA cycle mutants exhibited increased mortality and had higher bacterial burdens (1.5 log) during the course of the infection. These results suggest increasing the percentage of persister cells leads to increased tolerance to components of the innate immune system.