Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria

Abstract

Antibiotic resistance is a growing global health concern. Colistin is one of the last-resort antibiotics that treats multidrug-resistant (MDR) Gram-negative bacterial infection. However, bacteria resistant to colistin have become increasingly prevalent. Using a bacterial whole-cell screen of a fragment-based library, one compound was discovered to resensitize MDR Escherichia coli AR-0493 to colistin with low mammalian toxicity. Interestingly, postscreening validation studies identified a highly related yet distinct compound as the actual substance responsible for the activity. Further studies showed that this novel resistance-modifying agent is not only very potent but also highly selective to potentiate the activity of polymyxin family antibiotics in a wide range of MDR Gram-negative bacteria. Thus, it may be further developed as a combination therapy to prolong the life span of colistin in the clinic.

Figure 1

Structures of the top 3 hits from the colistin RMA screen.

Scheme 1. Synthesis of Compounds 1, 3, and 4

Figure 2

Checkerboard broth microdilution assay showed dose-dependent potentiation of colistin by compound 3 against MDR E. coli. AR-0493. Data represents the mean OD (600 nm) in two biological replicates.