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Sabine Ehrt^*, Michael U. Shiloh, Jia Ruan, Michael Choi^*, Stuart Gunzburg^*, Carl Nathan, Qiao-wen Xie, and Lee W. Riley^*

From the ^* Division of International Medicine and Infectious Disease and Division of Hematology-Oncology, Department of Medicine, Cornell University Medical College, New York 10021

Among the major antimicrobial products of macrophages are reactive intermediates of the oxidation of nitrogen (RNI) and the reduction of oxygen (ROI). Selection of recombinants in acidified nitrite led to the cloning of a novel gene, noxR1, from a pathogenic clinical isolate of Mycobacterium tuberculosis. Expression of noxR1 conferred upon Escherichia coli and Mycobacterium smegmatis enhanced ability to resist RNI and ROI, whether the bacteria were exposed to exogenous compounds in medium or to endogenous products in macrophages. These studies provide the first identification of an RNI resistance mechanism in mycobacteria, point to a new mechanism for resistance to ROI, and raise the possibility that inhibition of the noxR1 pathway might enhance the ability of macrophages to control tuberculosis.

This work was funded by National Institutes of Health (NIH) grant HL-51967 to L.W. Riley and C. Nathan; by a German Cancer Research Center fellowship to S. Ehrt; by a Richard Lounsbery Foundation fellowship to J. Ruan; and by NIH Medical Scientist Training Program grant GM-07739(MS) to M. Shiloh. We also acknowledge financial support from the Auxiliary of the Society of the New York Hospital for computer equipment.

¹ Abbreviations used in this paper: ASN, acidified sodium nitrite; GSNO, S-nitrosoglutathione; LB, Luria-Bertani; NADPH, nicotinamide adenine dinucleotide phosphate (reduced); NO, nitric oxide; NOS2, nitric oxide synthase type 2; ORF, open reading frame; pBS, pBluescript; RNI, reactive nitrogen intermediates; ROI, reactive oxygen intermediates; RT, reverse transcriptase.

C. Nathan and L.W. Riley contributed equally to this study.

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