Identification of the bacterial protein FtsX as a unique target of chemokine-mediated antimicrobial activity against Bacillus anthracis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (41), p.17159-17164
• Main Authors: Crawford, Matthew A., Lowe, David E., Fisher, Debra J., Stibitz, Scott, Plaut, Roger D., Beaber, John W., Zemansky, Jason, Mehrad, Borna, Glomski, Ian J., Strieter, Robert M., Hughes, Molly A.
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animals; Anthrax; Anti-Infective Agents - pharmacology; Antimicrobial activity; Antimicrobial agents; Antimicrobials; ATP binding cassette transporters; ATP-binding protein; Bacilli; Bacillus anthracis; Bacillus anthracis - drug effects; Bacillus anthracis - genetics; Bacillus anthracis - immunology; Bacillus anthracis - ultrastructure; Bacteria; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bactericidal activity; Biological Sciences; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - immunology; Cell Membrane - immunology; Cell Membrane - ultrastructure; Cell membranes; Chemokine CXCL10 - pharmacology; Chemokine CXCL10 - physiology; Chemokine CXCL9 - pharmacology; Chemokine CXCL9 - physiology; Chemokines; Chemokines, CXC - physiology; CXC chemokines; CXCL10 protein; Cytokines; Drug resistance; Drug Resistance, Microbial - genetics; Gene Deletion; Genes, Bacterial; Genetic Complementation Test; Gram-positive bacteria; Host-Pathogen Interactions - immunology; Humans; Infection; Infections; Mice; Microorganisms; Microscopy, Electron, Transmission; Molecular modelling; Mutation; Pathogens; Spore germination; Spores, Bacterial - drug effects; Spores, Bacterial - immunology; Transmembrane domains; Transposons
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1108495108

Chemokines are a family of chemotactic cytokines that function in host defense by orchestrating cellular movement during infection. In addition to this function, many chemokines have also been found to mediate the direct killing of a range of pathogenic microorganisms through an as-yet-undefined mechanism. As an understanding of the molecular mechanism and microbial targets of chemokine-mediated antimicrobial activity is likely to lead to the identification of unique, broad-spectrum therapeutic targets for effectively treating infection, we sought to investigate the mechanism by which the chemokine CXCL10 mediates bactericidal activity against the Gram-positive bacterium Bacillus anthracis, the causative agent of anthrax. Here, we report that disruption of the gene ftsX. which encodes the transmembrane domain of a putative ATP-binding cassette transporter, affords resistance to CXCL10-mediated antimicrobial effects against vegetative B. anthracis bacilli. Furthermore, we demonstrate that in the absence of FtsX, CXCL10 is unable to localize to its presumed site of action at the bacterial cell membrane, suggesting that chemokines interact with specific, identifiable bacterial components to mediate direct microbial killing. These findings provide unique insight into the mechanism of CXCL10-mediated bactericidal activity and establish, to our knowledge, the first description of a bacterial component critically involved in the ability of host chemokines to target and kill a bacterial pathogen. These observations also support the notion of chemokine-mediated antimicrobial activity as an important foundation for the development of innovative therapeutic strategies for treating infections caused by pathogenic, potentially multidrug-resistant microorganisms.