Introduction

By silico screening a library of natural compounds against the crystallographic structure of the ArnT protein, ent-beyer-15-en-18-O-oxalic acid (BBN149), a natural diterpene, and its natural derivatives or synthetics, have been identified as potential inhibitors of ArnT, responsible for the aminoribosylation of lipid A of LPS, one of the main mechanisms of resistance to colistin in bacteria.

Technical features

New inhibitors with a diterpene structure of resistance to colistin mediated by the aminoarabinosylation of lipid A catalyzed by the ArnT enzyme have been developed. Structural analogues of the lead compound were isolated from the plant and a series of semisynthetic derivatives were designed and synthesized to perform a structure-activity relationship (SAR) study. The most promising compound was found to be capable of increasing the efficacy of colistin up to 16 times against colistin-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae. The compound also showed low toxicity on human lung epithelial cells in vitro. The main advantage of the compounds of the invention is that they are active towards various bacterial species resistant to colistin whose resistance mechanism is mediated by ArnT. These include P. aeruginosa and K. pneumoniae in which the action of ArnT is the main mechanism of resistance to colistin. The invention responds to the problem of increasing the resistance of antibiotics in Gram-negative bacteria.

Possible Applications

• Pulmonary infections treatment;
• Pan-resistant Gram-negative bacterial infections, in which colistin resistance is mediated by ArnT.

Advantages

• Absence of relevant effects on susceptible strains;
• No toxicity on human cells;
• Active compounds against various bacterial species resistant to colistin whose resistance mechanism is mediated by ArnT;
• No cytotoxic effects on human lung cell models in vitro.