Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics
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 prev...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-09-01
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| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/8/4/163 |
| _version_ | 1818039054041612288 |
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| author | Kelly M. Lehman Marcin Grabowicz |
| author_facet | Kelly M. Lehman Marcin Grabowicz |
| author_sort | Kelly M. Lehman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T07:52:32Z |
| format | Article |
| id | doaj.art-6d27295192f148c380977d0888c45dde |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-12-10T07:52:32Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-6d27295192f148c380977d0888c45dde2022-12-22T01:56:59ZengMDPI AGAntibiotics2079-63822019-09-018416310.3390/antibiotics8040163antibiotics8040163Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel TherapeuticsKelly M. Lehman0Marcin Grabowicz1Microbiology and Molecular Genetics Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA 30322, USAMicrobiology and Molecular Genetics Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA 30322, USAGram-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.https://www.mdpi.com/2079-6382/8/4/163outer membraneBamALptDBamLptLolarylomycinglobomycin |
| spellingShingle | Kelly M. Lehman Marcin Grabowicz Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics Antibiotics outer membrane BamA LptD Bam Lpt Lol arylomycin globomycin |
| title | Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics |
| title_full | Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics |
| title_fullStr | Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics |
| title_full_unstemmed | Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics |
| title_short | Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics |
| title_sort | countering gram negative antibiotic resistance recent progress in disrupting the outer membrane with novel therapeutics |
| topic | outer membrane BamA LptD Bam Lpt Lol arylomycin globomycin |
| url | https://www.mdpi.com/2079-6382/8/4/163 |
| work_keys_str_mv | AT kellymlehman counteringgramnegativeantibioticresistancerecentprogressindisruptingtheoutermembranewithnoveltherapeutics AT marcingrabowicz counteringgramnegativeantibioticresistancerecentprogressindisruptingtheoutermembranewithnoveltherapeutics |