We describe a new technology, the Ibis T5000, for the identification of pathogens in clinical and environmental samples. The Ibis T5000 couples nucleic acid amplification to high-performance electrospray ionization mass spectrometry and base-composition analysis. The system enables the identification and quantification of a broad set of pathogens, including all known bacteria, all major groups of pathogenic fungi and the major families of viruses that cause disease in humans and animals, along with the detection of virulence factors and antibiotic resistance markers.

I. Introduction 377 II. Nucleic Acid Complexes 378 A. DNA Duplexes 378 1. Duplex Structure 379 2. DNA Duplex MS/MS 379 3. DNA Duplex H/D Exchange 380 B. DNA Triplexes and Quadruplexes 381 C. DNA−Protein Complexes 381 D. RNA−Protein Complexes 383 E. Macromolecular Complexes: Viruses, Ribosomes, and Beyond 384 F. DNA−Drug and Other DNA−Ligand Complexes 385 G. RNA−Ligand Complexes 387 1. TAR RNA 387 2. 16S A-site RNA 387 III. Future Directions 389 IV. Acknowledgments 389 V. References 389

For many years, analytical mass spectrometry has had numerous supporting roles in the drug development process, including the assessment of compound purity; quantitation of absorption, distribution, metabolism and excretion; and compound-specific pharmacokinetic analyses. More recently, mass spectrometry has emerged as an effective technique for identifying lead compounds on the basis of the characterization of noncovalent ligand-macromolecular target interactions. This approach offers several attractive properties for screening applications in drug discovery compared with other strategies, including the small quantities of target and ligands required, and the capacity to study ligands or targets without having to label them. Here, we review the application of electrospray ionization mass spectrometry to the interrogation of noncovalent complexes, highlighting examples from drug discovery efforts aimed at a range of target classes.

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