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.
Highlights
As the incidence of multidrug-resistant (MDR) bacteria rises, the discovery of new classes of antibiotics is integral to the continuation of modern medical practices [1]
A nuclear magnetic resonance (NMR) LptA–thanatin structure revealed the likely mechanism of action for thanatin: the inhibition of LptA complex formation with LptA, LptC, and LptD, all of which share a common OstA domain fold responsible for lipopolysaccharide transport (Lpt) bridge formation
Recent research has illustrated that the essential machines required for outer membrane (OM) biogenesis represent a bounty of potentially powerful therapeutic targets
Summary
As the incidence of multidrug-resistant (MDR) bacteria rises, the discovery of new classes of antibiotics is integral to the continuation of modern medical practices [1]. Small hydrophilic molecules can enter the cell through OMPs that function as non-specific porins through the OM bilayer Such molecules are often excreted through β-barrel or lipoprotein OM channels that are part of efflux pumps [6]. Bam, and Lol transport highly hydrophobic materials across the aqueous periplasm: LPS [8], β-barrel proteins [9], and lipoproteins [10], respectively. Since the OM is essential for the cell, the function of the Lpt, Bam, and Lol pathways is essential These pathways are comprised of more than a dozen essential and highly conserved proteins that provide new targets for antimicrobials. The further development of these lead molecules could provide antibiotics active against the growing threat of multidrug-resistant Gram-negative bacteria. The goal of this review is to emphasize the broad efforts targeting OM assembly and the discovery strategies that have proven successful in identifying OM-acting leads
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
