A novel antibiotic class targeting the lipopolysaccharide transporter

Abstract

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options1. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years1. Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB2FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB2FGC as a tractable target for antimicrobial drug development.

Using permeation guidelines to design new antibiotics—A PASsagE into Pseudomonas aeruginosa

“…39 As compounds predisposed to penetrate gram-negative bacteria are not present in standard screening collections, turning to other sources for novel chemical matter makes sense with recent successes in discovering interesting antibacterial leads through mining "unculturable" bacteria, 40 examining natural products produced by eukaryotic symbionts, 41 and using non-standard chemical matter. 42 A complimentary approach is chemically modifying a non-permeable antibiotic with functional groups that enhance accumulation; accumulation rules will guide such modifications and facilitate development of potent antibiotics.…”

Navigating Antibacterial Frontiers: A Panoramic Exploration of Antibacterial Landscapes, Resistance Mechanisms, and Emerging Therapeutic Strategies

“…For instance, A. baumannii is resistant to carbapenems because of a combination of decreased expression of porins, increased expression of three RND-type efflux pumps, and the presence of β-lactamases . A newly discovered antibiotic class, zosurabalpin, works by blocking a molecular machine called LptB2FGC that transports the lipopolysaccharide toxin from the inside barrier to the outside one and has shown efficacy in controlling carbapenem-resistant A. baumannii (CRAB) . Apart from resistance, certain bacteria also show “tolerance,” which is the ability of bacterial cells to withstand antibiotics due to them being in a physiological state of dormancy or slow growth .…”

“… 49 A newly discovered antibiotic class, zosurabalpin, works by blocking a molecular machine called LptB2FGC that transports the lipopolysaccharide toxin from the inside barrier to the outside one and has shown efficacy in controlling carbapenem-resistant A. baumannii (CRAB). 50 Apart from resistance, certain bacteria also show “tolerance,” which is the ability of bacterial cells to withstand antibiotics due to them being in a physiological state of dormancy or slow growth. 51 In addition, certain subpopulations of bacteria, known as “persisters,” are nongrowing and transiently tolerate antibiotic treatment.…”

“Multiplexed screen identifies aPseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS”

“…7 Examples are murepavadin (POL7080), a first-in-class antibiotic that targets the OM-localized lipopolysaccharide transport protein, LptD, in P. aeruginosa , 8 darobactin, a natural product that inhibits the OM β-barrel protein, BamA, 9 and zosurabalpin, a macrocyclic peptide that inhibits the inner membrane LPS transporter complex, LptB 2 FGC. 10,11…”