Role of Metal Availability in Modulating Antibiotic Efficacy

Understanding how host factors influence antibiotic efficacy is critical to preserving or enhancing treatment efficacy. The limitation of trace metals is a key aspect of the immune response, with the infection microenvironment depleted of essential metals through the action of host immune proteins. Here, we demonstrate that the limitation of zinc and manganese has opposing effects on β-lactam antibiotic efficacy against Staphylococcus aureus. Our results show that zinc chelation by the host immune protein calprotectin directly inactivates bacterial autolysins, zinc-dependent enzymes required for cell wall degradation and bacterial lysis following β-lactam treatment. Comparison of antibiotic efficacy in the presence and absence of calprotectin, both in vitro and in vivo, shows significantly decreased antibiotic killing under conditions of zinc limitation. On the other hand, in zinc-replete environments, manganese limitation was found to potentiate β-lactam antibiotic killing. Our data suggests that bacterial adaptation to intracellular oxidative stress under Mn-limiting conditions results in the increased expression and activity of bacterial autolysins, ultimately sensitizing S. aureus to antibiotic treatment. These findings demonstrate how zinc and manganese availability can dramatically influence the outcome of antibiotic treatment against S. aureus, highlighting a previously unrecognized determinant of antibiotic susceptibility for β-lactam antibiotics within the host.