A Clinically Selected Staphylococcus aureus <i>clpP</i> Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology
Lijuan Xu, Camilla Henriksen, Viktor Hundtofte Mebus, Romain Guérillot, Andreas Petersen, Nicolas Jacques, Jhih‐Hang Jiang, Rico J. E. Derks, Elena Sánchez‐López, Martin Giera, Kirsten Leeten, Timothy P. Stinear, Cécile Oury, Benjamin P. Howden, Anton Y. Peleg, Dorte Frees
Abstract
Daptomycin is a last-resort antibiotic used for the treatment of infections caused by Gram-positive antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Treatment failure is commonly linked to accumulation of point mutations; however, the contribution of single mutations to resistance and the mechanisms underlying resistance remain incompletely understood. Here, we show that a single nucleotide polymorphism (SNP) selected during daptomycin therapy inactivates the highly conserved ClpP protease and is causing reduced susceptibility of MRSA to daptomycin, vancomycin, and β-lactam antibiotics as well as decreased expression of virulence factors.