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Alkyl deoxyglycoside-polymyxin combinations against critical priority carbapenem-resistant gram-negative bacteria

2024-01-26Journal article Open access
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dc.contributor.authorMatos, Ana M. de
dc.contributor.authorCalado, Patrícia
dc.contributor.authorMiranda, Mónica
dc.contributor.authorAlmeida, Rita
dc.contributor.authorRauter, Amélia P.
dc.contributor.authorOliveira, M. Conceição
dc.contributor.authorManageiro, Vera
dc.contributor.authorCaniça, Manuela
dc.date.accessioned2025-02-28T11:59:59Z
dc.date.available2025-02-28T11:59:59Z
dc.date.issued2024-01-26
dc.description.abstractThe escalating antimicrobial resistance crisis urges the development of new antibacterial treatments with innovative mechanisms of action, particularly against the critical priority carbapenem-resistant Acinetobacter baumannii (CRAB), Pseudomonas aeruginosa (CRPA) and Enterobacteriaceae (CRE). Membrane-disrupting dodecyl deoxyglycosides have been reported for their interesting phosphatidylethanolamine-associated bactericidal activity against Gram-positive strains; however, their inability to penetrate the Gram-negative outer membrane (OM) renders them useless against the most challenging pathogens. Aiming to repurpose alkyl deoxyglycosides against Gram-negative bacteria, this study investigates the antimicrobial effects of five reference compounds with different deoxygenation patterns or anomeric configurations in combination with polymyxins as adjuvants for enhanced OM permeability. The generation of the lead 4,6-dideoxy scaffold was optimized through a simultaneous dideoxygenation step and applied to the synthesis of a novel alkyl 4,6-dideoxy C-glycoside 5, herein reported for the first time. When combined with subtherapeutic colistin concentrations, most glycosides demonstrated potent antimicrobial activity against several multidrug-resistant clinical isolates of CRAB, CRE and CRPA exhibiting distinct carbapenem resistance mechanisms, together with acceptable cytotoxicity against human HEK-293T and Caco-2 cells. The novel 4,6-dideoxy C-glycoside 5 emerged as the most promising prototype structure for further development (MIC 3.1 μg/mL when combined with colistin 0.5 μg/mL against CRPA or 0.25 μg/mL against several CRE and CRAB strains), highlighting the potential of C-glycosylation for an improved bioactive profile. This study is the first to show the potential of IM-targeting carbohydrate-based compounds for the treatment of infections caused by MDR Gram-negative pathogens of clinical importance.eng
dc.description.sponsorshipThis work was funded by FCT/MCTES (UIDB/00100/2020, LA/P/0056/2020 and UIDB/00211/2020) through national funds. A.M.M. also thanks FCT for funding through the Individual Call for Scientific Employment Stimulus (2022.07037.CEECIND).
dc.identifier.citationSci Rep . 2024 Jan 26;14(1):2219. doi: 10.1038/s41598-024-51428-6
dc.identifier.doi10.1038/s41598-024-51428-6
dc.identifier.eissn2045-2322
dc.identifier.pmid38278870
dc.identifier.urihttp://hdl.handle.net/10400.18/10401
dc.language.isoeng
dc.peerreviewedyes
dc.publisherNature Research
dc.relationCentro de Química Estrutural
dc.relationCenter for the Study of Animal Science
dc.relationLA/P/0056/2020
dc.relation2022.07037.CEECIND
dc.relation.hasversionhttps://www.nature.com/articles/s41598-024-51428-6
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAntibiotic Resistance
dc.subjectAntibacterial Activity
dc.subjectGlycoside‑colistin Combinations
dc.subjectResistência aos Antimicrobianos
dc.titleAlkyl deoxyglycoside-polymyxin combinations against critical priority carbapenem-resistant gram-negative bacteriaeng
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentro de Química Estrutural
oaire.awardTitleCenter for the Study of Animal Science
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00100%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00211%2F2020/PT
oaire.citation.issue14
oaire.citation.startPage2219
oaire.citation.titleScientific Reports
oaire.citation.volume26
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
relation.isProjectOfPublication86d45049-0a62-4f92-a7b0-4b0d7f14b0c2
relation.isProjectOfPublication69b75eb9-6f25-4ad8-98db-6cc7e9bcdcc7
relation.isProjectOfPublication.latestForDiscovery86d45049-0a62-4f92-a7b0-4b0d7f14b0c2

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