{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:28:54Z","timestamp":1790634534767,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UI\/BD\/153078\/2022"],"award-info":[{"award-number":["UI\/BD\/153078\/2022"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/04631\/2021"],"award-info":[{"award-number":["SFRH\/BD\/04631\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/00329\/2020"],"award-info":[{"award-number":["UIDP\/00329\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective pressure that triggers the emergence of multi-drug resistance. We performed a large-scale analysis of closed bacterial genomes to identify multi-drug resistance considering the ResFinder antimicrobial classes. We found that more than 95% of the genomes harbor genes associated with resistance to disinfectants, glycopeptides, macrolides, and tetracyclines. On average, each genome encodes resistance to more than nine different classes of antimicrobial drugs. We found higher-than-expected co-occurrences of resistance genes in both plasmids and chromosomes for several classes of antibiotic resistance, including classes categorized as critical according to the World Health Organization (WHO). As a result of antibiotic-resistant priority pathogens, higher-than-expected co-occurrences appear in plasmids, increasing the potential for resistance dissemination. For the first time, co-occurrences of antibiotic resistance have been investigated for priority pathogens as defined by the WHO. For critically important pathogens, co-occurrences appear in plasmids, not in chromosomes, suggesting that the resistances may be epidemic and probably recent. These results hint at the need for new approaches to treating infections caused by critically important bacteria.<\/jats:p>","DOI":"10.3390\/ijms241411438","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T08:35:47Z","timestamp":1689323747000},"page":"11438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Multi-Drug Resistance in Bacterial Genomes\u2014A Comprehensive Bioinformatic Analysis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2970-010X","authenticated-orcid":false,"given":"C\u00e9lia P. F.","family":"Domingues","sequence":"first","affiliation":[{"name":"cE3c\u2014Centre for Ecology, Evolution and Environmental Changes & CHANGE, Global Change and Sustainability Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"INIAV\u2014National Institute for Agrarian and Veterinary Research, 2780-157 Oeiras, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8662-7378","authenticated-orcid":false,"given":"Jo\u00e3o S.","family":"Rebelo","sequence":"additional","affiliation":[{"name":"cE3c\u2014Centre for Ecology, Evolution and Environmental Changes & CHANGE, Global Change and Sustainability Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3653-1511","authenticated-orcid":false,"given":"Francisco","family":"Dionisio","sequence":"additional","affiliation":[{"name":"cE3c\u2014Centre for Ecology, Evolution and Environmental Changes & CHANGE, Global Change and Sustainability Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Nogueira","sequence":"additional","affiliation":[{"name":"cE3c\u2014Centre for Ecology, Evolution and Environmental Changes & CHANGE, Global Change and Sustainability Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"INIAV\u2014National Institute for Agrarian and Veterinary Research, 2780-157 Oeiras, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"ref_1","first-page":"56","article-title":"The Treasure Called Antibiotics","volume":"14","author":"Adedeji","year":"2016","journal-title":"Ann. Ib. Postgrad. Med."},{"key":"ref_2","unstructured":"WHO (2019). New Report Calls for Urgent-Action to Avert Antimicrobial Resistance Crisis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41396-020-00780-2","article-title":"Air Pollution Could Drive Global Dissemination of Antibiotic Resistance Genes","volume":"15","author":"Zhu","year":"2021","journal-title":"ISME J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.ijheh.2019.03.006","article-title":"Antibiotic Resistant Bacteria and Resistance Genes in Biofilms in Clinical Wastewater Networks","volume":"222","author":"Sib","year":"2019","journal-title":"Int. J. Hyg. Environ. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7593","DOI":"10.1128\/AEM.00736-15","article-title":"The Ocean as a Global Reservoir of Antibiotic Resistance Genes","volume":"81","author":"Hatosy","year":"2015","journal-title":"Appl. Env. Microbiol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1089\/mdr.2015.0072","article-title":"Low Prevalence of Carbapenem-Resistant Bacteria in River Water: Resistance Is Mostly Related to Intrinsic Mechanisms","volume":"21","author":"Correia","year":"2015","journal-title":"Microb. Drug Resist."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Nogueira, T., and Botelho, A. (2021). Metagenomics and Other Omics Approaches to Bacterial Communities and Antimicrobial Resistance Assessment in Aquacultures. Antibiotics, 10.","DOI":"10.3390\/antibiotics10070787"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Silva, D.G., Domingues, C.P.F., Figueiredo, J.F., Dionisio, F., Botelho, A., and Nogueira, T. (2022). Estuarine Aquacultures at the Crossroads of Animal Production and Antibacterial Resistance: A Metagenomic Approach to the Resistome. Biology, 11.","DOI":"10.3390\/biology11111681"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100230","DOI":"10.1016\/j.coesh.2021.100230","article-title":"Antibiotic Resistance in the Soil Ecosystem: A One Health Perspective","volume":"20","author":"Wang","year":"2021","journal-title":"Curr. Opin. Environ. Sci. Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"22989","DOI":"10.1007\/s11356-021-17339-z","article-title":"Antibiotic Resistance of Fecal Carriage of Escherichia Coli from Pig Farms in China: A Meta-Analysis","volume":"29","author":"Li","year":"2022","journal-title":"Env. Sci. Pollut. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/2052-336X-11-12","article-title":"A Novel Approach for Pathogen Reduction in Wastewater Treatment","volume":"11","author":"Periasamy","year":"2013","journal-title":"J. Env. Health Sci. Eng."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20140083","DOI":"10.1098\/rstb.2014.0083","article-title":"Antimicrobial Resistance in Humans, Livestock and the Wider Environment","volume":"370","author":"Woolhouse","year":"2015","journal-title":"Phil. Trans. R. Soc. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1038\/s41396-019-0478-9","article-title":"Viruses as Key Reservoirs of Antibiotic Resistance Genes in the Environment","volume":"13","author":"Debroas","year":"2019","journal-title":"ISME J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4600","DOI":"10.1128\/AEM.00872-15","article-title":"Bacteriophages Isolated from Chicken Meat and the Horizontal Transfer of Antimicrobial Resistance Genes","volume":"81","author":"Shousha","year":"2015","journal-title":"Appl. Env. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.tim.2006.02.006","article-title":"Co-Selection of Antibiotic and Metal Resistance","volume":"14","author":"Wright","year":"2006","journal-title":"Trends Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e00135-19","DOI":"10.1128\/mSphere.00135-19","article-title":"Antibiotic Resistance Gene Diversity and Virulence Gene Diversity Are Correlated in Human Gut and Environmental Microbiomes","volume":"4","author":"Escudeiro","year":"2019","journal-title":"mSphere"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"142702","DOI":"10.1016\/j.scitotenv.2020.142702","article-title":"Co-Selection of Antibiotic Resistance Genes, and Mobile Genetic Elements in the Presence of Heavy Metals in Poultry Farm Environments","volume":"755","author":"Mazhar","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jhazmat.2012.07.040","article-title":"Antibiotic Resistance Gene Abundances Associated with Antibiotics and Heavy Metals in Animal Manures and Agricultural Soils Adjacent to Feedlots in Shanghai; China","volume":"235\u2013236","author":"Ji","year":"2012","journal-title":"J. Hazard. Mater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1021\/acs.est.6b05342","article-title":"Comparison of Metals and Tetracycline as Selective Agents for Development of Tetracycline Resistant Bacterial Communities in Agricultural Soil","volume":"51","author":"Song","year":"2017","journal-title":"Environ. Sci. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s00128-014-1383-6","article-title":"Co-Occurrence of Antibiotic and Heavy Metal Resistance in K\u0131z\u0131l\u0131rmak River Isolates","volume":"93","author":"Icgen","year":"2014","journal-title":"Bull Env. Contam Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3844\/ajidsp.2015.41.47","article-title":"Screening of Multi-Drug and Metal Resistant Aeromonas Species from Diverse Sources","volume":"11","author":"Amsaveni","year":"2015","journal-title":"Am. J. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Domingues, C.P.F., Rebelo, J.S., Pothier, J., Monteiro, F., Nogueira, T., and Dionisio, F. (2021). The Perfect Condition for the Rising of Superbugs: Person-to-Person Contact and Antibiotic Use Are the Key Factors Responsible for the Positive Correlation between Antibiotic Resistance Gene Diversity and Virulence Gene Diversity in Human Metagenomes. Antibiotics, 10.","DOI":"10.3390\/antibiotics10050605"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Dionisio, F., Domingues, C.P.F., Rebelo, J.S., Monteiro, F., and Nogueira, T. (2023). The Impact of Non-Pathogenic Bacteria on the Spread of Virulence and Resistance Genes. IJMS, 24.","DOI":"10.3390\/ijms24031967"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Darmancier, H., Domingues, C.P.F., Rebelo, J.S., Amaro, A., Dion\u00edsio, F., Pothier, J., Serra, O., and Nogueira, T. (2022). Are Virulence and Antibiotic Resistance Genes Linked? A Comprehensive Analysis of Bacterial Chromosomes and Plasmids. Antibiotics, 11.","DOI":"10.3390\/antibiotics11060706"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"835403","DOI":"10.3389\/fmicb.2022.835403","article-title":"Genetic Diversity, Distribution, and Genomic Characterization of Antibiotic Resistance and Virulence of Clinical Pseudomonas Aeruginosa Strains in Kenya","volume":"13","author":"Kiyaga","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jgar.2021.02.020","article-title":"A Global Perspective on the Convergence of Hypervirulence and Carbapenem Resistance in Klebsiella Pneumoniae","volume":"25","author":"Lan","year":"2021","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/j.1365-2958.2006.05520.x","article-title":"Horizontal Transfer of Virulence Genes Encoded on the Enterococcus Faecalis Pathogenicity Island: Transfer of PAI-Encoded Virulence Genes in E. Faecalis","volume":"63","author":"Coburn","year":"2007","journal-title":"Mol. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S1473-3099(10)70143-2","article-title":"Emergence of a New Antibiotic Resistance Mechanism in India, Pakistan, and the UK: A Molecular, Biological, and Epidemiological Study","volume":"10","author":"Kumarasamy","year":"2010","journal-title":"Lancet Infect Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1128\/AAC.45.7.2054-2059.2001","article-title":"Effect of Abolishment of the Use of Antimicrobial Agents for Growth Promotion on Occurrence of Antimicrobial Resistance in Fecal Enterococci from Food Animals in Denmark","volume":"45","author":"Aarestrup","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Li, X., Brejnrod, A., Trivedi, U., Russel, J., Stokholm, J., Thorsen, J., Shah, S.A., Vestergaard, G.A., Rasmussen, M.A., and Nesme, J. (2023). Co-Localization of Antibiotic Resistance Genes Is Widespread in the Infant Gut Microbiome and Associates with an Immature Gut Microbial Composition. bioRxiv.","DOI":"10.1101\/2023.02.19.525876"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Martiny, H.-M., Munk, P., Brinch, C., Aarestrup, F.M., Calle, M.L., and Petersen, T.N. (2022). Utilizing Co-Abundances of Antimicrobial Resistance Genes to Identify Potential Co-Selection in the Resistome. bioRxiv.","DOI":"10.1101\/2022.12.19.519133"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1093\/jac\/dkm171","article-title":"Characterization of the IncA\/C Plasmid PCC416 Encoding VIM-4 and CMY-4 \u03b2-Lactamases","volume":"60","author":"Colinon","year":"2007","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1093\/jac\/dkx488","article-title":"Plasmids Carrying Antimicrobial Resistance Genes in Enterobacteriaceae","volume":"73","author":"Rozwandowicz","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Carattoli, A., Seiffert, S.N., Schwendener, S., Perreten, V., and Endimiani, A. (2015). Differentiation of IncL and IncM Plasmids Associated with the Spread of Clinically Relevant Antimicrobial Resistance. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123063"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/j.tim.2018.06.007","article-title":"Evolution of Plasmid-Mediated Antibiotic Resistance in the Clinical Context","volume":"26","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.ijmm.2013.02.001","article-title":"Plasmids and the Spread of Resistance","volume":"303","author":"Carattoli","year":"2013","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10311-013-0404-8","article-title":"Tetracycline Antibiotics in the Environment: A Review","volume":"11","author":"Daghrir","year":"2013","journal-title":"Env. Chem. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/j.addr.2005.04.002","article-title":"Bacterial Resistance to Antibiotics: Enzymatic Degradation and Modification","volume":"57","author":"Wright","year":"2005","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/hdy.2017.33","article-title":"Social Behaviour Involving Drug Resistance: The Role of Initial Density, Initial Frequency and Population Structure in Shaping the Effect of Antibiotic Resistance as a Public Good","volume":"119","author":"Domingues","year":"2017","journal-title":"Heredity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1126\/science.1099390","article-title":"Bacterial Persistence as a Phenotypic Switch","volume":"305","author":"Balaban","year":"2004","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.mib.2014.06.016","article-title":"Persistence: A Copacetic and Parsimonious Hypothesis for the Existence of Non-Inherited Resistance to Antibiotics","volume":"21","author":"Levin","year":"2014","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rebelo, J.S., Domingues, C.P., Monteiro, F., Nogueira, T., and Dionisio, F. (2021). Bacterial Persistence Is Essential for Susceptible Cell Survival in Indirect Resistance, Mainly for Lower Cell Densities. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246500"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.tim.2022.12.010","article-title":"Psychological and Cultural Factors Influencing Antibiotic Prescription","volume":"31","author":"Dionisio","year":"2023","journal-title":"Trends Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1093\/jac\/dkaa345","article-title":"ResFinder 4.0 for Predictions of Phenotypes from Genotypes","volume":"75","author":"Bortolaia","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkn201","article-title":"NCBI BLAST: A Better Web Interface","volume":"36","author":"Johnson","year":"2008","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/14\/11438\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:11:54Z","timestamp":1760127114000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/14\/11438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,14]]},"references-count":45,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["ijms241411438"],"URL":"https:\/\/doi.org\/10.3390\/ijms241411438","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,14]]}}}