Cell envelope structural and functional contributions to antibiotic resistance in Burkholderia cenocepacia
Antibiotic activity is limited by the physical construction of the Gram-negative cell envelope. Species of the complex (Bcc) are known as intrinsically multidrug-resistant opportunistic pathogens with low permeability cell envelopes. Here, we re-examined a previously performed chemical-genetic scree...
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| Veröffentlicht in: | Journal of bacteriology 2024-04, Vol.206 (4), p.e0044123 |
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| creator | Hogan, Andrew M Motnenko, Anna Rahman, A S M Zisanur Cardona, Silvia T |
| description | Antibiotic activity is limited by the physical construction of the Gram-negative cell envelope. Species of the
complex (Bcc) are known as intrinsically multidrug-resistant opportunistic pathogens with low permeability cell envelopes. Here, we re-examined a previously performed chemical-genetic screen of barcoded transposon mutants in
K56-2, focusing on cell envelope structural and functional processes. We identified structures mechanistically important for resistance to singular and multiple antibiotic classes. For example, susceptibility to novobiocin, avibactam, and the LpxC inhibitor, PF-04753299, was linked to the BpeAB-OprB efflux pump, suggesting these drugs are substrates for this pump in
. Defects in peptidoglycan precursor synthesis specifically increased susceptibility to cycloserine and revealed a new putative amino acid racemase, while defects in divisome accessory proteins increased susceptibility to multiple β-lactams. Additionally, disruption of the periplasmic disulfide bond formation system caused pleiotropic defects on outer membrane integrity and β-lactamase activity. Our findings highlight the layering of resistance mechanisms in the structure and function of the cell envelope. Consequently, we point out processes that can be targeted for developing antibiotic potentiators.IMPORTANCEThe Gram-negative cell envelope is a double-layered physical barrier that protects cells from extracellular stressors, such as antibiotics. The
cell envelope is known to contain additional modifications that reduce permeability. We investigated
cell envelope factors contributing to antibiotic resistance from a genome-wide view by re-examining data from a transposon mutant library exposed to an antibiotic panel. We identified susceptible phenotypes for defects in structures and functions in the outer membrane, periplasm, and cytoplasm. Overall, we show that resistance linked to the cell envelope is multifaceted and provides new targets for the development of antibiotic potentiators. |
| doi_str_mv | 10.1128/jb.00441-23 |
| format | Article |
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complex (Bcc) are known as intrinsically multidrug-resistant opportunistic pathogens with low permeability cell envelopes. Here, we re-examined a previously performed chemical-genetic screen of barcoded transposon mutants in
K56-2, focusing on cell envelope structural and functional processes. We identified structures mechanistically important for resistance to singular and multiple antibiotic classes. For example, susceptibility to novobiocin, avibactam, and the LpxC inhibitor, PF-04753299, was linked to the BpeAB-OprB efflux pump, suggesting these drugs are substrates for this pump in
. Defects in peptidoglycan precursor synthesis specifically increased susceptibility to cycloserine and revealed a new putative amino acid racemase, while defects in divisome accessory proteins increased susceptibility to multiple β-lactams. Additionally, disruption of the periplasmic disulfide bond formation system caused pleiotropic defects on outer membrane integrity and β-lactamase activity. Our findings highlight the layering of resistance mechanisms in the structure and function of the cell envelope. Consequently, we point out processes that can be targeted for developing antibiotic potentiators.IMPORTANCEThe Gram-negative cell envelope is a double-layered physical barrier that protects cells from extracellular stressors, such as antibiotics. The
cell envelope is known to contain additional modifications that reduce permeability. We investigated
cell envelope factors contributing to antibiotic resistance from a genome-wide view by re-examining data from a transposon mutant library exposed to an antibiotic panel. We identified susceptible phenotypes for defects in structures and functions in the outer membrane, periplasm, and cytoplasm. Overall, we show that resistance linked to the cell envelope is multifaceted and provides new targets for the development of antibiotic potentiators.</description><identifier>ISSN: 0021-9193</identifier><identifier>ISSN: 1098-5530</identifier><identifier>EISSN: 1098-5530</identifier><identifier>DOI: 10.1128/jb.00441-23</identifier><identifier>PMID: 38501654</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>Amino acids ; Anti-Bacterial Agents - pharmacology ; Antibiotic resistance ; Antibiotics ; Biosynthesis ; Burkholderia - metabolism ; Burkholderia cenocepacia - genetics ; Burkholderia cepacia complex - genetics ; Cell envelopes ; Cycloserine ; Defects ; Drug resistance ; Drug Resistance, Multiple, Bacterial - genetics ; Editor’s Pick ; Efflux ; Genetic screening ; Microbial Sensitivity Tests ; Multidrug resistance ; Mutagenesis ; Novobiocin ; Opportunist infection ; Peptidoglycans ; Permeability ; Physiology and Metabolism ; Research Article ; Structure-function relationships ; Substrates ; β Lactamase ; β-Lactam antibiotics</subject><ispartof>Journal of bacteriology, 2024-04, Vol.206 (4), p.e0044123</ispartof><rights>Copyright © 2024 American Society for Microbiology.</rights><rights>Copyright American Society for Microbiology Apr 2024</rights><rights>Copyright © 2024 American Society for Microbiology. 2024 American Society for Microbiology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a364t-ae49094120379a6982c33fbc421af65da513fff65fca60a67054722dc84452ef3</cites><orcidid>0000-0002-0782-012X ; 0000-0002-0629-8886</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11025338/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11025338/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38501654$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Galperin, Michael Y.</contributor><creatorcontrib>Hogan, Andrew M</creatorcontrib><creatorcontrib>Motnenko, Anna</creatorcontrib><creatorcontrib>Rahman, A S M Zisanur</creatorcontrib><creatorcontrib>Cardona, Silvia T</creatorcontrib><title>Cell envelope structural and functional contributions to antibiotic resistance in Burkholderia cenocepacia</title><title>Journal of bacteriology</title><addtitle>J Bacteriol</addtitle><addtitle>J Bacteriol</addtitle><description>Antibiotic activity is limited by the physical construction of the Gram-negative cell envelope. Species of the
complex (Bcc) are known as intrinsically multidrug-resistant opportunistic pathogens with low permeability cell envelopes. Here, we re-examined a previously performed chemical-genetic screen of barcoded transposon mutants in
K56-2, focusing on cell envelope structural and functional processes. We identified structures mechanistically important for resistance to singular and multiple antibiotic classes. For example, susceptibility to novobiocin, avibactam, and the LpxC inhibitor, PF-04753299, was linked to the BpeAB-OprB efflux pump, suggesting these drugs are substrates for this pump in
. Defects in peptidoglycan precursor synthesis specifically increased susceptibility to cycloserine and revealed a new putative amino acid racemase, while defects in divisome accessory proteins increased susceptibility to multiple β-lactams. Additionally, disruption of the periplasmic disulfide bond formation system caused pleiotropic defects on outer membrane integrity and β-lactamase activity. Our findings highlight the layering of resistance mechanisms in the structure and function of the cell envelope. Consequently, we point out processes that can be targeted for developing antibiotic potentiators.IMPORTANCEThe Gram-negative cell envelope is a double-layered physical barrier that protects cells from extracellular stressors, such as antibiotics. The
cell envelope is known to contain additional modifications that reduce permeability. We investigated
cell envelope factors contributing to antibiotic resistance from a genome-wide view by re-examining data from a transposon mutant library exposed to an antibiotic panel. We identified susceptible phenotypes for defects in structures and functions in the outer membrane, periplasm, and cytoplasm. Overall, we show that resistance linked to the cell envelope is multifaceted and provides new targets for the development of antibiotic potentiators.</description><subject>Amino acids</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibiotic resistance</subject><subject>Antibiotics</subject><subject>Biosynthesis</subject><subject>Burkholderia - metabolism</subject><subject>Burkholderia cenocepacia - genetics</subject><subject>Burkholderia cepacia complex - genetics</subject><subject>Cell envelopes</subject><subject>Cycloserine</subject><subject>Defects</subject><subject>Drug resistance</subject><subject>Drug Resistance, Multiple, Bacterial - genetics</subject><subject>Editor’s Pick</subject><subject>Efflux</subject><subject>Genetic screening</subject><subject>Microbial Sensitivity Tests</subject><subject>Multidrug resistance</subject><subject>Mutagenesis</subject><subject>Novobiocin</subject><subject>Opportunist infection</subject><subject>Peptidoglycans</subject><subject>Permeability</subject><subject>Physiology and Metabolism</subject><subject>Research Article</subject><subject>Structure-function relationships</subject><subject>Substrates</subject><subject>β Lactamase</subject><subject>β-Lactam antibiotics</subject><issn>0021-9193</issn><issn>1098-5530</issn><issn>1098-5530</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1vEzEQxS1ERdPAiTuyxAUJbfHnZn1CEFGoVIkLnK1Zr029bOzgj0r89zi0BFpxGo_m6ed58xB6Tsk5pWx4M4_nhAhBO8YfoRUlauik5OQxWhHCaKeo4qfoLOeZECqEZE_QKR8kob0UKzRv7bJgG27sEvcW55KqKTXBgiFM2NVgio-htSaGkvxYD23GJbZ58aOPxRucbPa5QDAW-4Df1_T9Oi6TTR6wsSEauwfj4Sk6cbBk--yurtHXiw9ftp-6q88fL7fvrjrgvSgdWKGIEpQRvlHQq4EZzt1oBKPgejmBpNy59nIGegL9hkixYWwyw8GcdXyN3t5y93Xc2altUJofvU9-B-mnjuD1_Unw1_pbvNGUEiY5Hxrh1R0hxR_V5qJ3Ppt2KAg21qyZ6gfFOKe0SV8-kM6xpnawrDkRB4lqZY1e36pMijkn647bUKIPIep51L9D1A17_B7yjv3l_V_64l-vR-yfgPkvofel_Q</recordid><startdate>20240418</startdate><enddate>20240418</enddate><creator>Hogan, Andrew M</creator><creator>Motnenko, Anna</creator><creator>Rahman, A S M Zisanur</creator><creator>Cardona, Silvia T</creator><general>American Society for Microbiology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0782-012X</orcidid><orcidid>https://orcid.org/0000-0002-0629-8886</orcidid></search><sort><creationdate>20240418</creationdate><title>Cell envelope structural and functional contributions to antibiotic resistance in Burkholderia cenocepacia</title><author>Hogan, Andrew M ; Motnenko, Anna ; Rahman, A S M Zisanur ; Cardona, Silvia T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a364t-ae49094120379a6982c33fbc421af65da513fff65fca60a67054722dc84452ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Amino acids</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antibiotic resistance</topic><topic>Antibiotics</topic><topic>Biosynthesis</topic><topic>Burkholderia - metabolism</topic><topic>Burkholderia cenocepacia - genetics</topic><topic>Burkholderia cepacia complex - genetics</topic><topic>Cell envelopes</topic><topic>Cycloserine</topic><topic>Defects</topic><topic>Drug resistance</topic><topic>Drug Resistance, Multiple, Bacterial - genetics</topic><topic>Editor’s Pick</topic><topic>Efflux</topic><topic>Genetic screening</topic><topic>Microbial Sensitivity Tests</topic><topic>Multidrug resistance</topic><topic>Mutagenesis</topic><topic>Novobiocin</topic><topic>Opportunist infection</topic><topic>Peptidoglycans</topic><topic>Permeability</topic><topic>Physiology and Metabolism</topic><topic>Research Article</topic><topic>Structure-function relationships</topic><topic>Substrates</topic><topic>β Lactamase</topic><topic>β-Lactam antibiotics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hogan, Andrew M</creatorcontrib><creatorcontrib>Motnenko, Anna</creatorcontrib><creatorcontrib>Rahman, A S M Zisanur</creatorcontrib><creatorcontrib>Cardona, Silvia T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of bacteriology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hogan, Andrew M</au><au>Motnenko, Anna</au><au>Rahman, A S M Zisanur</au><au>Cardona, Silvia T</au><au>Galperin, Michael Y.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cell envelope structural and functional contributions to antibiotic resistance in Burkholderia cenocepacia</atitle><jtitle>Journal of bacteriology</jtitle><stitle>J Bacteriol</stitle><addtitle>J Bacteriol</addtitle><date>2024-04-18</date><risdate>2024</risdate><volume>206</volume><issue>4</issue><spage>e0044123</spage><pages>e0044123-</pages><issn>0021-9193</issn><issn>1098-5530</issn><eissn>1098-5530</eissn><abstract>Antibiotic activity is limited by the physical construction of the Gram-negative cell envelope. Species of the
complex (Bcc) are known as intrinsically multidrug-resistant opportunistic pathogens with low permeability cell envelopes. Here, we re-examined a previously performed chemical-genetic screen of barcoded transposon mutants in
K56-2, focusing on cell envelope structural and functional processes. We identified structures mechanistically important for resistance to singular and multiple antibiotic classes. For example, susceptibility to novobiocin, avibactam, and the LpxC inhibitor, PF-04753299, was linked to the BpeAB-OprB efflux pump, suggesting these drugs are substrates for this pump in
. Defects in peptidoglycan precursor synthesis specifically increased susceptibility to cycloserine and revealed a new putative amino acid racemase, while defects in divisome accessory proteins increased susceptibility to multiple β-lactams. Additionally, disruption of the periplasmic disulfide bond formation system caused pleiotropic defects on outer membrane integrity and β-lactamase activity. Our findings highlight the layering of resistance mechanisms in the structure and function of the cell envelope. Consequently, we point out processes that can be targeted for developing antibiotic potentiators.IMPORTANCEThe Gram-negative cell envelope is a double-layered physical barrier that protects cells from extracellular stressors, such as antibiotics. The
cell envelope is known to contain additional modifications that reduce permeability. We investigated
cell envelope factors contributing to antibiotic resistance from a genome-wide view by re-examining data from a transposon mutant library exposed to an antibiotic panel. We identified susceptible phenotypes for defects in structures and functions in the outer membrane, periplasm, and cytoplasm. Overall, we show that resistance linked to the cell envelope is multifaceted and provides new targets for the development of antibiotic potentiators.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>38501654</pmid><doi>10.1128/jb.00441-23</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-0782-012X</orcidid><orcidid>https://orcid.org/0000-0002-0629-8886</orcidid></addata></record> |
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| subjects | Amino acids Anti-Bacterial Agents - pharmacology Antibiotic resistance Antibiotics Biosynthesis Burkholderia - metabolism Burkholderia cenocepacia - genetics Burkholderia cepacia complex - genetics Cell envelopes Cycloserine Defects Drug resistance Drug Resistance, Multiple, Bacterial - genetics Editor’s Pick Efflux Genetic screening Microbial Sensitivity Tests Multidrug resistance Mutagenesis Novobiocin Opportunist infection Peptidoglycans Permeability Physiology and Metabolism Research Article Structure-function relationships Substrates β Lactamase β-Lactam antibiotics |
| title | Cell envelope structural and functional contributions to antibiotic resistance in Burkholderia cenocepacia |
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