N-Hydroxyformamide LpxC inhibitors, their in vivo efficacy in a mouse Escherichia coli infection model, and their safety in a rat hemodynamic assay

Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020

“…Additionally, ACHN-975 chelates the catalytic zinc of LpxC with hydroxamic acid, which is associated with the release of toxic metabolic by-products and off-target inhibition ( 100 , 132 – 134 ). However, replacing the moiety impairs inhibitory potency and antibacterial activity with persisting toxicity ( 135 , 136 ), underscoring the need for probing structure-toxicity relationships in new antibiotic classes. Conceivably, in vivo preclinical models are good predictors of antibacterial efficacy but poor predictors of safety, and alternate methods for assessing structure-toxicity relationships in vitro and in vivo should be developed.…”

Structure–Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors

“…UDP-3- O -( R -3-hydroxymyristoyl)- N -acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first, committed step in the biosynthesis of lipid A, a fatty acylated glucosamine disaccharide that anchors lipopolysaccharide (LPS) to the outer membrane of Gram-negative bacteria. − Given that LPS is an essential cell wall component in most Gram-negative pathogens, LpxC is a promising target for antibacterial discovery and many LpxC inhibitors have been developed, the majority of which contain a hydroxamate functional group that chelates the catalytic zinc ion. − Some of these compounds are shown in Figure and include molecules from Merck (L-161,240), Chiron (Chiron-090), and British Biotech (BB-78485) . In addition, several companies including Achaogen, , Pfizer, Novartis, , Entasis, and Taisho Pharma have developed LpxC inhibitors that have in vivo activity in animal models of infection, while the Achaogen compound ACHN-975 was also evaluated in a Phase I clinical trial . However, despite highly promising in vitro and in vivo activity, no LpxC inhibitor has progressed through clinical trials, and efforts are needed to widen the therapeutic window of LpxC inhibitors.…”

“…Representative LpxC inhibitors. Biological and microbiological data was taken from the following literature sources: CHIR-090, BB-78485, ACHN-975, L-161,240, PF5081090, TP0586532, Entasis (compound 19 ), Novartis Compound 1 (+/−), and Novartis compound 13f …”

“…10−13 Some of these compounds are shown in Figure 1 and include molecules from Merck (L-161,240), 14 Chiron (Chiron-090), 15 and British Biotech (BB-78485). 16 In addition, several companies including Achaogen, 17,18 Pfizer, 19 Novartis, 20,21 Entasis, 22 and Taisho Pharma 23 have developed LpxC inhibitors that have in vivo activity in animal models of infection, while the Achaogen compound ACHN-975 was also evaluated in a Phase I clinical trial. 18 However, despite highly promising in vitro and in vivo activity, no LpxC inhibitor has progressed through clinical trials, and efforts are needed to widen the therapeutic window of LpxC inhibitors.…”

Structure-Based Ligand Design Targeting Pseudomonas aeruginosa LpxA in Lipid A Biosynthesis

“… Lipid A is the essential and antigenic component of LPS, and enzymes involved in its assembly have thus served as the focus of many drug discovery efforts. Of the first six essential enzymes (LpxA, LpxC, LpxD, LpxH/I/G, LpxB, and LpxK) in the lipid A biosynthesis pathway, LpxC has been most extensively targeted. − The bactericidal potency of LpxC inhibitors is comparable to ampicillin . Unfortunately, the clinical success of current LpxC inhibitors has thus far been limited by cardiovascular toxicity, preventing advancement past phase I trials. , …”