Eradication of Bacterial Persisters with Antibiotic-Generated Hydroxyl Radicals
Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals Sarah Schmidt Grant a,b,c,1, Benjamin B. Kaufmanna,c,d,1, Nikhilesh S. Chandd,e, Nathan Haseleya,d,f, and Deborah T. Hunga,b,c,d,2 aBroad Institute of MIT and Harvard, Cambridge, MA 02142; bDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02114; cDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; dDepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; eDepartment of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; and fHarvard–MIT Division of Health Sciences and Technology, Cambridge, MA 02139 Edited by* Eric S. Lander, Broad Institute of MIT and Harvard, Cambridge, MA, and approved June 11, 2012 (received for review March 2, 2012) During Mycobacterium tuberculosis infection, a population of bac- terial cell numbers but do not sterilize the mouse (8). A plateau teria likely becomes refractory to antibiotic killing in the absence of is typically reached during which numbers of viable bacteria genotypic resistance, making treatment challenging. We describe stabilize. In addition to the mouse infection model, the inability an in vitro model capable of yielding a phenotypically antibi- to sterilize has been observed in the zebra fish (Mycobacterium otic-tolerant subpopulation of cells, often called persisters, within marinum), guinea pig (M. tuberculosis), and macrophage populations of Mycobacterium smegmatis and M. tuberculosis.We (M. tuberculosis) infection models (9–11). In vitro, the survival find that persisters are distinct from the larger antibiotic-suscepti- of a similar small subpopulation can also be observed when ble population, as a small drop in dissolved oxygen (DO) satura- a culture is exposed to high doses of antibiotics (12, 13).
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