Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics

Abstract

Gram-negative bacteria shield themselves from antibiotics by producing an outer membrane (OM) that forms a formidable permeability barrier. Multidrug resistance among these organisms is a particularly acute problem that is exacerbated by the OM. The poor penetrance of many available antibiotics prevents their clinical use, and efforts to discover novel classes of antibiotics against Gram-negative bacteria have been unsuccessful for almost 50 years. Recent insights into how the OM is built offer new hope. Several essential multiprotein molecular machines (Bam, Lpt, and Lol) work in concert to assemble the barrier and offer a swathe of new targets for novel therapeutic development. Murepavadin has been at the vanguard of these efforts, but its recently reported phase III clinical trial toxicity has tempered the anticipation of imminent new clinical options. Nonetheless, the many concerted efforts aimed at breaking down the OM barrier provide a source of ongoing optimism for what may soon come through the development pipeline. We will review the current state of drug development against the OM assembly targets, highlighting insightful new discovery approaches and strategies.

Novel inhibitors ofE. colilipoprotein diacylglyceryl transferase are insensitive to resistance caused bylppdeletion

“…We used a combination of biochemical and genetic strategies ( death. This hypothesis is actually consistent with data using globomycin or an improved analog ,G0790, which binds a highly conserved active site (Vogeley et al, 2016) and for which no ontarget resistance mutations have ever been described (Lehman & Grabowicz, 2019;. As recent publications have revealed significant insights into the potential mechanisms of diacylglyceryl modification by Lgt (Mao et al, 2016;Singh et al, 2019), further studies aimed at determining if these Lgti competitively inhibit binding of the phosphatidylglycerol or prolipoprotein substrates would be critical in better understanding the mechanism by which these molecules interfere with this critical OM biogenesis pathway.…”

Thanatin Impairs Lipopolysaccharide Transport Complex Assembly by Targeting LptC–LptA Interaction and Decreasing LptA Stability

“…Overall, our results highlight OM biogenesis as an excellent target for novel antibiotic discovery. Thanatin joins the increasing list of molecules that disrupt the assembly of the OM with diverse mechanisms (Hart et al, 2019;Imai et al, 2019;Lehman and Grabowicz, 2019;Psonis et al, 2019). Based on their mechanisms, these compounds could be employed not only to fight multidrug resistant pathogens but also in combination with existing antibiotics not sufficiently effective.…”

“…Moreover, two compounds targeting the MsbA-mediated IM translocation process have been recently reported (Ho et al, 2018;Zhang et al, 2018). However, the only inhibitor of LPS biogenesis to have entered, so far, Phase III trials is Murepavadin, a macrocyclic peptidomimetic selectively directed against Pseudomonas aeruginosa LptD (Srinivas et al, 2010;Lehman and Grabowicz, 2019). Unfortunately, the clinical trials have been suspended recently due to nephrotoxicity (Lehman and Grabowicz, 2019).…”

“…However, the only inhibitor of LPS biogenesis to have entered, so far, Phase III trials is Murepavadin, a macrocyclic peptidomimetic selectively directed against Pseudomonas aeruginosa LptD (Srinivas et al, 2010;Lehman and Grabowicz, 2019). Unfortunately, the clinical trials have been suspended recently due to nephrotoxicity (Lehman and Grabowicz, 2019). Nevertheless, the identification of Murepavadin highlights the Lpt machinery as a good target for the discovery of molecules endowed with antibacterial activity.…”

The Mla pathway in Acinetobacter baumannii has no demonstrable role in anterograde lipid transport

“…When taking these factors into consideration, it is unsurprising that the OM has remained one of the largest hurdles in an increasingly desperate race for antimicrobial discovery ( Lehman and Grabowicz, 2019 ; Luepke and Mohr, 2017 ). A large majority of antibiotic classes are ineffective on Gram-negative bacteria due to either the inability to diffuse across the membrane ( Nikaido, 1994 ; Vergalli et al, 2020 ) or rapid efflux out of the cytoplasmic space ( Du et al, 2018 ).…”