Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline

Abstract

This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.

Mutations Reducing In Vitro Susceptibility to Novel LpxC Inhibitors in Pseudomonas aeruginosa and Interplay of Efflux and Nonefflux Mechanisms

“…1), and since then many others have been reported (7,18,19). Recent examples from our group include compound 1 (9) and compound 2 (oxazolidinone 13f), compound 3 (isoxazoline 25d), and compound 4 (isoxazoline 25e) described previously (12) (Fig. 1) that have potent in vitro activity against P. aeruginosa.…”

“…Along with being a key factor in establishing the permeability barrier of the OM, LPS is also essential for growth and virulence in many Gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Targets in the lipid A biosynthetic pathway, in particular LpxC (7)(8)(9)(10)(11)(12), or in the machinery that transports LPS and assembles it in the OM (13) have been the focus of intense drug discovery efforts. Early efforts to identify LpxC inhibitors yielded compounds that had activity against E. coli but not P. aeruginosa (14), raising the possibility that these inhibitors did not accumulate sufficiently in P. aeruginosa (as is often the case) or that LpxC was not essential in this pathogen.…”

“…We also noted that in vitro passaging of cells in the presence of CHIR-090 can lead to cumulative and substantial reductions in susceptibility. Here, we used single-step mutant selections and passaging approaches, along with targeted and genome sequencing, to examine the role of efflux and nonefflux mechanisms in mediating decreased susceptibility to CHIR-090 and the more recently described LpxC inhibitors compound 1 (9), compound 2 (oxazolidinone 13f), compound 3 (isoxazoline 25d), and compound 4 (isoxazoline 25e) (12) (Fig. 1) that have potent in vitro activity against P. aeruginosa.…”

Synthesis, antibacterial and anticancer activity, and docking study of aminoguanidines containing an alkynyl moiety

“…Since the discovery of L-161240 as the first LpxC inhibitor in the 1990s 11 , many LpxC inhibitors have been reported as antibacterial agents [6][7][8] . Most LpxC inhibitors share common structural features that mimic the natural Zn 2þ -binding substrate: (1) a hydroxamate head group, (2) a central linker, and (3) a lipophilic tail 12 . Among the well-characterised compounds, threonyl-hydroxamate derivatives, such as CHIR-12 and LPC-009, are representative LpxC inhibitors [13][14][15] .…”

Two distinct mechanisms of small molecule inhibition of LpxA acyltransferase essential for lipopolysaccharide biosynthesis

“…17 Since lipid A is essential for growth and structural integrity of most Gram-negative bacteria, small molecule inhibitors of lipid A biosynthesis prevent growth or restore the activity of antibiotics with intracellular targets that could not otherwise be reached. 14–15, 18 Furthermore, inhibition of lipid A biosynthesis can reduce the levels of endotoxin that are released during antibiotic treatment. 19 Therefore, lipid A biosynthesis has been viewed as a promising target for the discovery of new antibacterials.…”