The emergence of multi-drug resistance to carbapenems, extended spectrum beta-lactamases, the antifolate trimethoprim, fluoroquinolones and aminoglycosides by gram negative Enterobacteriaceae pathogens underscores the dwindling antibiotic armory. Antifolates lag behind the other classes of drugs in terms of generational improvements to combat drug resistance. With improved potency of Propargyl Linked Antifolates (PLA’s) against MRSA1, screening against gram-negative species engendered a 1,3 benzodioxole based pharmacophore as potent ligand with an enzymatic and cellular activity of 47nM and 1.5μg/mL respectively. The 8 fold and 260 fold gain in potency against the AcrB and LPS knocked-out strain of E.coli highlights the twin issues of efflux and permeability, limiting our efficacy against the wild type E.Coli. Using a refined retrosynthetic strategy for higher throughput, efforts were directed towards modulating the C-ring of PLA’s to understand the physicochemical properties governing the efflux and permeability issues. While a shift from heteroaromatic C ring to substituted phenyl ring lowered the efflux activity, studies are being carried out to overcome the permeability barrier. References 1. Viswanathan, K.; Frey, K.M.; Scocchera, E.W.; Martin, B.D.; Swain,W.; Alverson, J.B.; Priestley, N.D.; Anderson, A.C.; Wright, D.L. PLoS One, 2012, 7,e29434.

Bolstering the antibacterial arsenal: Propargyl linked antifolates for gram negative pathogens

251st National Meeting (2016)

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