Non-Traditional Antibacterial Screening Approaches for the Identification of Novel Inhibitors of the Glyoxylate Shunt in Gram-Negative Pathogens

• DOI: 10.1371/journal.pone.0051732
• Publication Date: 2012-12-11T21:50:03Z
• Authors: Kelly C. Fahnoe; Mark E. Flanagan; Glenn Gibson; Veerabahu Shanmug...; Ye Che; Andrew P. Tomaras
• Keywords: Phenotypic screening; Chemical space

Antibacterial compounds that affect bacterial viability have traditionally been identified, confirmed, and characterized in standard laboratory media. The historical success of identifying new antibiotics via this route has justifiably established a traditional means screening for antimicrobials. emergence multi-drug-resistant (MDR) pathogens expedited the need antibiotics, though many industry questioned source(s) these compounds. As pharmaceutical companies' chemical libraries exhaustively screened route, we concluded all with any antibacterial potential identified. While compound platforms are being pursued, it also seems prudent to screen currently hand using alternative approaches. One strategy involves under conditions better reflect environment experience during an infection, vivo essential targets pathways dispensable growth media vitro. Here describe novel inhibit glyoxylate shunt Pseudomonas aeruginosa, pathway is required survival pulmonary environment. We demonstrate compounds, which were not previously identified approaches, broad-spectrum activity when they tested vivo-relevant conditions. show potent on both enzymes comprise shunt, feature was supported by computational homology modeling. By dual-targeting pathway, would expect see reduced propensity resistance development Taken together, data suggest understanding must tolerate, adjusting paradigm those conditions, could identify treatment serious MDR pathogens.