Advances and challenges in bacterial compound accumulation assays for drug discovery

• Published in: Current opinion in chemical biology 2018-06, Vol.44, p.9-15
• Main Authors: Six, David A, Krucker, Thomas, Leeds, Jennifer A
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - analysis; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Drug Discovery - methods; Gram-Negative Bacteria - cytology; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - metabolism; Gram-Negative Bacterial Infections - drug therapy; Gram-Negative Bacterial Infections - microbiology; Humans; Models, Molecular; Permeability
• ISSN: 1367-5931; 1879-0402
• DOI: 10.1016/j.cbpa.2018.05.005

The identification of potent in vitro inhibitors of essential bacterial targets is relatively straightforward, however vanishingly few of these molecules have Gram-negative antibacterial potency and spectrum because of a failure to accumulate inside the bacteria. The Gram-negative bacterial cell envelope provides a formidable barrier to entry and couples with efflux pumps to prevent compound accumulation. Assays to measure the cellular permeation, efflux and accumulation of compounds in bacteria continue to be innovated and refined to guide drug discovery. Important advances in the label-free detection of compounds associated with or passing through bacteria rely on mass spectrometry This technique holds the promise of bacterial subcellular resolution and the throughput needed to test libraries of compounds to evaluate structure-accumulation relationships.