Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration

• Published in: mBio 2024-07, Vol.15 (7), p.e0138924
• Main Authors: Reyes Ruiz, Valeria M, Freiberg, Jeffrey A, Weiss, Andy, Green, Erin R, Jobson, Mary-Elizabeth, Felton, Emily, Shaw, Lindsey N, Chazin, Walter J, Skaar, Eric P
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacteriology; calprotectin; clpP; Endopeptidase Clp - genetics; Endopeptidase Clp - metabolism; Gene Expression Regulation, Bacterial; Leukocyte L1 Antigen Complex - metabolism; Metals - metabolism; Mice; nutritional immunity; Research Article; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - genetics; Staphylococcus aureus - metabolism
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.01389-24

The host protein calprotectin inhibits the growth of a variety of bacterial pathogens through metal sequestration in a process known as "nutritional immunity." growth is inhibited by calprotectin , and calprotectin is localized to staphylococcal abscesses during infection. However, the staphylococcal adaptations that provide defense against nutritional immunity and the role of metal-responsive regulators are not fully characterized. In this work, we define the transcriptional response of and the role of the metal-responsive regulators, Zur, Fur, and MntR, in response to metal limitation by calprotectin exposure. Additionally, we identified genes affecting the fitness of during metal limitation through a Transposon sequencing (Tn-seq) approach. Loss of function mutations in , which encodes a proteolytic subunit of the ATP-dependent Clp protease, demonstrate reduced fitness of to the presence of calprotectin. ClpP contributes to pathogenesis in a calprotectin-dependent manner. These studies establish a critical role for ClpP to combat metal limitation by calprotectin and reveal the genes required for to outcompete the host for metals. is a leading cause of skin and soft tissue infections, bloodstream infections, and endocarditis. Antibiotic treatment failures during infections are increasingly prevalent, highlighting the need for novel antimicrobial agents. Metal chelator-based therapeutics have tremendous potential as antimicrobials due to the strict requirement for nutrient metals exhibited by bacterial pathogens. The high-affinity transition metal-binding properties of calprotectin represents a potential therapeutic strategy that functions through metal chelation. Our studies provide a foundation to define mechanisms by which combats nutritional immunity and may be useful for the development of novel therapeutics to counter the ability of to survive in a metal-limited environment.