{"doi":"10.1101/2021.07.21.453182","title":"Colistin resistance in\n                  <i>Escherichia coli</i>\n                  confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Colistin is a polymyxin antibiotic of last resort for the treatment of infections caused by multi-drug resistant Gram-negative bacteria. By targeting lipopolysaccharide (LPS), the antibiotic disrupts both the outer and cytoplasmic membranes, leading to lysis and bacterial death. Colistin resistance in\n                  <jats:italic>Escherichia coli</jats:italic>\n                  occurs via mutations in the chromosome or the acquisition of mobilised colistin resistance (\n                  <jats:italic>mcr</jats:italic>\n                  ) genes. Both these colistin resistance mechanisms result in chemical modifications to the LPS, with positively charged moieties added at the cytoplasmic membrane before the LPS is transported to the outer membrane. We have previously shown that MCR-1-mediated LPS modification protects the cytoplasmic but not the outer membrane from damage caused by colistin, enabling bacterial survival. However, it remains unclear whether this observation extends to colistin resistance conferred by other\n                  <jats:italic>mcr</jats:italic>\n                  genes, or resistance due to chromosomal mutations. Using a panel of clinical\n                  <jats:italic>E. coli</jats:italic>\n                  that had acquired\n                  <jats:italic>mcr</jats:italic>\n                  -1, -1.5, -2, -3, -3.2 or -5, or had acquired polymyxin resistance independently of\n                  <jats:italic>mcr</jats:italic>\n                  genes, we found that almost all isolates were susceptible to colistin-mediated permeabilisation of the outer, but not cytoplasmic, membrane. Furthermore, we showed that permeabilisation of the outer membrane of colistin resistant isolates by the polymyxin is in turn sufficient to sensitise bacteria to the antibiotic rifampicin, which normally cannot cross the LPS monolayer. These findings demonstrate that colistin resistance in\n                  <jats:italic>E. coli</jats:italic>\n                  is typically due to protection of the cytoplasmic but not outer membrane from colistin-mediated damage, regardless of the mechanism of resistance.\n                </jats:p>","journal":null,"year":null,"id":664232,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":660340,"name":"Gerald Larrouy‐Maumus","orcid":"0000-0001-6614-8698","position":1,"is_corresponding":false},{"id":867752,"name":"R. Christopher D. Furniss","orcid":"0000-0002-5806-5099","position":2,"is_corresponding":false},{"id":484688,"name":"Despoina A. I. Mavridou","orcid":"0000-0002-7449-1151","position":3,"is_corresponding":false},{"id":1233855,"name":"Akshay Sabnis","orcid":"0000-0002-8131-0128","position":4,"is_corresponding":false},{"id":484690,"name":"Andrew M. Edwards","orcid":"0000-0002-7173-7355","position":5,"is_corresponding":false},{"id":1734357,"name":"Madeleine Humphrey","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Colistin resistance in\n                  <i>Escherichia coli</i>\n                  confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Colistin is a polymyxin antibiotic of last resort for the treatment of infections caused by multi-drug resistant Gram-negative bacteria. By targeting lipopolysaccharide (LPS), the antibiotic disrupts both the outer and cytoplasmic membranes, leading to lysis and bacterial death. Colistin resistance in\n                  <jats:italic>Escherichia coli</jats:italic>\n                  occurs via mutations in the chromosome or the acquisition of mobilised colistin resistance (\n                  <jats:italic>mcr</jats:italic>\n                  ) genes. Both these colistin resistance mechanisms result in chemical modifications to the LPS, with positively charged moieties added at the cytoplasmic membrane before the LPS is transported to the outer membrane. We have previously shown that MCR-1-mediated LPS modification protects the cytoplasmic but not the outer membrane from damage caused by colistin, enabling bacterial survival. However, it remains unclear whether this observation extends to colistin resistance conferred by other\n                  <jats:italic>mcr</jats:italic>\n                  genes, or resistance due to chromosomal mutations. Using a panel of clinical\n                  <jats:italic>E. coli</jats:italic>\n                  that had acquired\n                  <jats:italic>mcr</jats:italic>\n                  -1, -1.5, -2, -3, -3.2 or -5, or had acquired polymyxin resistance independently of\n                  <jats:italic>mcr</jats:italic>\n                  genes, we found that almost all isolates were susceptible to colistin-mediated permeabilisation of the outer, but not cytoplasmic, membrane. Furthermore, we showed that permeabilisation of the outer membrane of colistin resistant isolates by the polymyxin is in turn sufficient to sensitise bacteria to the antibiotic rifampicin, which normally cannot cross the LPS monolayer. These findings demonstrate that colistin resistance in\n                  <jats:italic>E. coli</jats:italic>\n                  is typically due to protection of the cytoplasmic but not outer membrane from colistin-mediated damage, regardless of the mechanism of resistance.\n                </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34723787","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"UK Research and Innovation","grant_id":"MR/M009505/1","title":"Characterisation of disulfide bond formation in bacterial pathogens: Unravelling the adaptation of a classical pathway into a virulence aid."},{"funder_name":"Wenner-Gren Foundations","grant_id":"unidentified","title":"unidentified"},{"funder_name":"UK Research and Innovation","grant_id":"MR/N014103/1","title":"DTP Bid Led by Imperial College London"},{"funder_name":"Wellcome Trust","grant_id":"105603","title":"Institutional Strategic Support Fund Phase2 FY2014/16"}],"total_grants":4,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"CC BY","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2021/07/21/2021.07.21.453182.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2021.07.21.453182","host_type":"publisher"},{"url":"https://doi.org/10.1101/2021.07.21.453182","host_type":""},{"url":"https://doi.org/10.1099/mic.0.001104","host_type":""},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743629","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/34723787","host_type":""},{"url":"http://dx.doi.org/10.1099/mic.0.001104","host_type":""},{"url":"https://dx.doi.org/10.1099/mic.0.001104","host_type":""},{"url":"https://dx.doi.org/10.1101/2021.07.21.453182","host_type":""},{"url":"https://doi.org/https://doi.org/10.1099/mic.0.001104","host_type":""}],"fields_of_study":["0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["570","Drug Resistance","Microbial Sensitivity Tests","SUSCEPTIBILITY","Microbiology","MECHANISMS","resistance","616","Drug Resistance, Bacterial","Escherichia coli","colistin","Polymyxins","Antimicrobials and AMR","Science & Technology","Escherichia coli Proteins","lipopolysaccharide","polymyxin","E. coli","Bacterial","Anti-Bacterial Agents","INFECTIONS","MCR","INACTIVATION","Life Sciences & Biomedicine","Plasmids"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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