{"paper_id":"2b2a3d9a-3e1d-4592-b526-b5be03bafe97","body_text":"Convergent evolution of antibiotic resistance mechanisms between synthetic pyrrolobenzodiazepines (PBDs) and the naturally occurring albicidin in multidrug resistant Klebsiella pneumoniae | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Convergent evolution of antibiotic resistance mechanisms between synthetic pyrrolobenzodiazepines (PBDs) and the naturally occurring albicidin in multidrug resistant Klebsiella pneumoniae Yasmin Miriam Surani, Matthew Wand, Pietro Picconi, Michele Di Palma, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4901630/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Klebsiella pneumoniae is designated as one of six priority ESKAPE pathogens by the World Health Organisation (WHO). It is the causative agent of a number of serious infections, including pneumonia, and worryingly strains are known to have resistance to the four major antibiotic classes. Pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic heterocycle have been developed as a new class of potent antibacterial compounds. They are active against multidrug resistant (MDR) Gram-negative pathogens, including K. pneumoniae . When K. pneumoniae isolates were exposed to PBDs, they acquired resistance, with an increase in minimum inhibitory concentration (MIC) from 1-4 µg/mL to >32 µg/mL. Resistant strains showed mutations in genes associated with resistance to the phytotoxin albicidin, specifically tsx and merR -family regulator albA . Heterologous expression of AlbA in Escherichia coli , and introduction of a proposed resistance-mediating single-nucleotide polymorphism (SNP) (AlbA L120Q) into the genome of a sensitive K. pneumoniae strain confers both PBD and albicidin resistance. Given the parallels between these two structurally unrelated compound classes, these mechanisms may offer resistance to further antibiotics in K. pneumoniae and should be considered in future antibiotic discovery. Biological sciences/Drug discovery Biological sciences/Evolution Biological sciences/Genetics Biological sciences/Microbiology Biological sciences/Molecular biology Biological sciences/Structural biology Klebsiella pneumoniae Gram-negative bacteria multidrug resistance pyrrolobenzodiazepines (PBDs) albicidin antimicrobial resistance Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 20 Sep, 2024 Reviewers agreed at journal 18 Sep, 2024 Reviewers agreed at journal 18 Sep, 2024 Reviewers invited by journal 03 Sep, 2024 Editor assigned by journal 15 Aug, 2024 Submission checks completed at journal 14 Aug, 2024 First submitted to journal 12 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4901630\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":351100654,\"identity\":\"6870d132-6a63-4942-9d20-4095ed2ad3f8\",\"order_by\":0,\"name\":\"Yasmin Miriam 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It is the causative agent of a number of serious infections, including pneumonia, and worryingly strains are known to have resistance to the four major antibiotic classes. Pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic heterocycle have been developed as a new class of potent antibacterial compounds. They are active against multidrug resistant (MDR) Gram-negative pathogens, including \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e. When \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e isolates were exposed to PBDs, they acquired resistance, with an increase in minimum inhibitory concentration (MIC) from 1-4 µg/mL to \\u0026gt;32 µg/mL. Resistant strains showed mutations in genes associated with resistance to the phytotoxin albicidin, specifically \\u003cem\\u003etsx\\u003c/em\\u003eand \\u003cem\\u003emerR\\u003c/em\\u003e-family regulator \\u003cem\\u003ealbA\\u003c/em\\u003e. Heterologous expression of AlbA in \\u003cem\\u003eEscherichia coli\\u003c/em\\u003e, and introduction of a proposed resistance-mediating single-nucleotide polymorphism (SNP) (AlbA L120Q) into the genome of a sensitive \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e strain confers both PBD and albicidin resistance. Given the parallels between these two structurally unrelated compound classes, these mechanisms may offer resistance to further antibiotics in \\u003cem\\u003eK. pneumoniae\\u003c/em\\u003e and should be considered in future antibiotic discovery.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Convergent evolution of antibiotic resistance mechanisms between synthetic pyrrolobenzodiazepines (PBDs) and the naturally occurring albicidin in multidrug resistant Klebsiella pneumoniae\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-09-11 11:39:53\",\"doi\":\"10.21203/rs.3.rs-4901630/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-09-20T08:49:24+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"192945470997371208869748834494289239473\",\"date\":\"2024-09-18T10:39:31+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"331624038710434921021544773331890641425\",\"date\":\"2024-09-18T07:13:13+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-09-03T15:30:05+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-08-15T10:08:11+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-08-14T13:36:11+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"npj Antimicrobials and Resistance\",\"date\":\"2024-08-12T15:27:52+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"npj-antimicrobials-and-resistance\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"npjamar\",\"sideBox\":\"Learn more about [npj Antimicrobials and Resistance](http://www.nature.com/npjamar/)\",\"snPcode\":\"44259\",\"submissionUrl\":\"https://submission.springernature.com/new-submission/44259/3\",\"title\":\"npj Antimicrobials and Resistance\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"NPJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"1f762705-0422-49ff-a709-6df49c4b16e1\",\"owner\":[],\"postedDate\":\"September 11th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[{\"id\":37281404,\"name\":\"Biological sciences/Drug discovery\"},{\"id\":37281405,\"name\":\"Biological sciences/Evolution\"},{\"id\":37281406,\"name\":\"Biological sciences/Genetics\"},{\"id\":37281407,\"name\":\"Biological sciences/Microbiology\"},{\"id\":37281408,\"name\":\"Biological sciences/Molecular biology\"},{\"id\":37281409,\"name\":\"Biological sciences/Structural biology\"}],\"tags\":[],\"updatedAt\":\"2025-04-09T09:08:12+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2024-09-11 11:39:53\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4901630\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4901630\",\"identity\":\"rs-4901630\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}