{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T06:25:09Z","timestamp":1761719109856,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The search for new antibacterial agents has become urgent due to the exponential growth of bacterial resistance to antibiotics. Nitrogen-containing heterocycles such as 1,8-naphthyridine derivatives have been shown to have excellent antimicrobial properties. Therefore, the purpose of this study was to evaluate the antibacterial and antibiotic-modulating activities of 1,8-naphthyridine derivatives against multi-resistant bacterial strains. The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of the following compounds: 7-acetamido-1,8-naphthyridin-4(1H)-one and 3-trifluoromethyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide. The antibiotic-modulating activity was analyzed using subinhibitory concentrations (MIC\/8) of these compounds in combination with norfloxacin, ofloxacin, and lomefloxacin. Multi-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were used in both tests. Although the compounds had no direct antibacterial activity (MIC \u2265 1.024 \u00b5g\/mL), they could decrease the MIC of these fluoroquinolones, indicating synergism was obtained from the association of the compounds. These results suggest the existence of a structure\u2013activity relationship in this group of compounds with regard to the modulation of antibiotic activity. Therefore, we conclude that 1,8-naphthyridine derivatives potentiate the activity of fluoroquinolone antibiotics against multi-resistant bacterial strains, and thereby interesting candidates for the development of drugs against bacterial infections caused by multidrug resistant strains.<\/jats:p>","DOI":"10.3390\/molecules26237400","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T22:18:42Z","timestamp":1638829122000},"page":"7400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Enhancement of Antibiotic Activity by 1,8-Naphthyridine Derivatives against Multi-Resistant Bacterial Strains"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1240-3654","authenticated-orcid":false,"given":"Jos\u00e9 B. de","family":"Ara\u00fajo-Neto","sequence":"first","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology (LMBM), Regional University of Cariri\u2014URCA, Crato 63105-000, CE, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0676-4813","authenticated-orcid":false,"given":"Maria M. C. da","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology (LMBM), Regional University of Cariri\u2014URCA, Crato 63105-000, CE, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1316-7064","authenticated-orcid":false,"given":"C\u00edcera D. de M.","family":"Oliveira-Tintino","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology (LMBM), Regional University of Cariri\u2014URCA, Crato 63105-000, CE, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I\u00eada M.","family":"Begnini","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Regional University of Blumenau\u2014FURB, Itoupava Seca, Blumenau 89012-900, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1362-1837","authenticated-orcid":false,"given":"Ricardo A.","family":"Rebelo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Regional University of Blumenau\u2014FURB, Itoupava Seca, Blumenau 89012-900, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luiz E. da","family":"Silva","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Sustainable Territorial Development\u2014Coastal Sector, Federal University of Paran\u00e1, Curitiba 80060-000, PR, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandro L.","family":"Mireski","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Regional University of Blumenau\u2014FURB, Itoupava Seca, Blumenau 89012-900, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9953-9430","authenticated-orcid":false,"given":"Michele C.","family":"Nasato","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Regional University of Blumenau\u2014FURB, Itoupava Seca, Blumenau 89012-900, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria I. L.","family":"Krautler","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Regional University of Blumenau\u2014FURB, Itoupava Seca, Blumenau 89012-900, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3126-6509","authenticated-orcid":false,"given":"Jaime","family":"Ribeiro-Filho","sequence":"additional","affiliation":[{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ\/BA), Rua Waldemar Falc\u00e3o, 121, Candeal, Salvador 40296-710, BA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abolghasem","family":"Siyadatpanah","sequence":"additional","affiliation":[{"name":"Ferdows School of Paramedical and Health, Birjand University of Medical Sciences, Birjand 9717853577, Iran"},{"name":"Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand 9717853577, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2730-7788","authenticated-orcid":false,"given":"Polrat","family":"Wilairatana","sequence":"additional","affiliation":[{"name":"Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6634-4207","authenticated-orcid":false,"given":"Henrique D. M.","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology (LMBM), Regional University of Cariri\u2014URCA, Crato 63105-000, CE, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saulo R.","family":"Tintino","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology and Molecular Biology (LMBM), Regional University of Cariri\u2014URCA, Crato 63105-000, CE, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ribeiro Da Cunha, B., Fonseca, L.P., and Calado, C.R.C. (2019). Antibiotic discovery: Where have we come from, where do we go?. Antibiotics, 8.","DOI":"10.3390\/antibiotics8020045"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.mib.2019.10.008","article-title":"Antibiotics: Past, present and future","volume":"51","author":"Hutchings","year":"2019","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20200105","DOI":"10.1098\/rsif.2020.0105","article-title":"Factors favouring the evolution of multidrug resistance in bacteria","volume":"17","author":"Jacopin","year":"2020","journal-title":"J. R. Soc. Interface"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/nrmicro3380","article-title":"Molecular mechanisms of antibiotic resistance","volume":"13","author":"Blair","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Varela, M.F., Stephen, J., Lekshmi, J., Ojha, M., Wenzel, N., Sanford, L.M., Hernandez, A.J., Parvathi, A., and Kumar, S.H. (2021). Bacterial Resistance to Antimicrobial Agents. Antibiotics, 10.","DOI":"10.3390\/antibiotics10050593"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.3389\/fmicb.2020.01669","article-title":"The demand for new antibiotics: Antimicrobial peptides, nanoparticles, and combinatorial therapies as future strategies in antibacterial agent design","volume":"11","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_8","first-page":"66","article-title":"A review: Biological significances of heterocyclic compounds","volume":"4","author":"Saini","year":"2013","journal-title":"Int. J. Pharm. Sci. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1016\/j.tetlet.2014.11.046","article-title":"Nature loves nitrogen heterocycles","volume":"56","author":"Walsh","year":"2015","journal-title":"Tetrahedron Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6611","DOI":"10.1039\/C6OB00936K","article-title":"Modern advances in heterocyclic chemistry in drug discovery","volume":"14","author":"Taylor","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4968","DOI":"10.1016\/j.bmcl.2013.06.048","article-title":"Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines","volume":"23","author":"Parhi","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.36468\/pharmaceutical-sciences.621","article-title":"Synthesis, Biological Evaluation and Molecular Docking Studies of Novel 1,8-Naphthyridine-3-carboxylic Acid Derivatives as Potential Antimicrobial Agents (Part-1)","volume":"82","author":"Gurjar","year":"2020","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1128\/AAC.01218-07","article-title":"The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral","volume":"52","author":"Garvey","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3356","DOI":"10.1016\/j.ejmech.2009.03.015","article-title":"1,8-Naphthyridine-3-carboxamide derivatives with anticancer and anti-inflammatory activity","volume":"44","author":"Kumar","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.ejmech.2019.06.033","article-title":"2,7-naphthyridinone-based MET kinase inhibitors: A promising novel scaffold for antitumor drug development","volume":"178","author":"Zhuo","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ejmech.2009.10.020","article-title":"1,8-Naphthyridines VIII. Novel 5-aminoimidazo [1,2-a][1,8] naphthyridine-6-carboxamide and 5-amino [1,2,4] triazolo [4,3-a][1,8] naphthyridine-6-carboxamide derivatives showing potent analgesic or anti-inflammatory activity, respectively, and completely devoid of acute gastrolesivity","volume":"45","author":"Roma","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Abu-Melha, S., Edrees, M.M., Salem, H.H., Kheder, N.A., Gomha, S.M., and Abdelaziz, M.R. (2019). Synthesis and biological evaluation of some novel thiazole-based heterocycles as potential anticancer and antimicrobial agents. Molecules, 24.","DOI":"10.3390\/molecules24030539"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1021\/jm970202e","article-title":"Novel Fluoroquinolone Antibacterial Agents Containing Oxime-Substituted (Aminomethyl) pyrrolidines: Synthesis and Antibacterial Activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic Acid (LB20304), 1","volume":"40","author":"Hong","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_19","first-page":"2375","article-title":"Synthesis, characterization and antimicrobial activities of fused 1, 6-naphthyridines","volume":"44","author":"Suresh","year":"2005","journal-title":"Indian J. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jep.2007.01.032","article-title":"Uses and abuses of in vitro tests in ethnopharmacology: Visualizing an elephant","volume":"110","author":"Houghton","year":"2007","journal-title":"J. Ethnopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1800141","DOI":"10.1002\/ardp.201800141","article-title":"Recent updates of fluoroquinolones as antibacterial agents","volume":"351","author":"Ezelarab","year":"2018","journal-title":"Arch. Pharmaz."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bonev, B.B., and Brown, N.M. (2019). Fluoroquinolone resistance. Bacterial Resistance to Antibiotics\u2013From Molecules to Man, John Wiley & Sons. [1st ed.].","DOI":"10.1002\/9781119593522"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"a025320","DOI":"10.1101\/cshperspect.a025320","article-title":"Topoisomerase inhibitors: Fluoroquinolone mechanisms of action and resistance","volume":"6","author":"Hooper","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"154","DOI":"10.2174\/157018007779422550","article-title":"Synthesis and antiparasitic activity against Trypanosoma cruzi and Leishmania amazonensis of chlorinated 1,7- and 1,8-naphthyridines","volume":"4","author":"Steindel","year":"2007","journal-title":"Lett. Drug Des. Discov."},{"key":"ref_25","unstructured":"Nasato, M.C. (2017). 1,8-naftiridinas Sulfonam\u00eddicas: Obten\u00e7\u00e3o, Caracteriza\u00e7\u00e3o e Avalia\u00e7\u00e3o Antiprotozo\u00e1ria e Antif\u00fangica. [Master\u2019s Thesis, Funda\u00e7\u00e3o Universidade Regional de Blumenau]."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1016\/j.bmcl.2015.03.044","article-title":"Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2)","volume":"25","author":"Singh","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5355","DOI":"10.1016\/j.bmcl.2009.07.129","article-title":"Spiro-naphthyridinone piperidines as inhibitors of S. aureus and E. coli enoyl-ACP reductase (FabI)","volume":"19","author":"Sampson","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s00044-013-0604-6","article-title":"Synthesis, molecular docking of novel 1,8-naphthyridine derivatives and their cytotoxic activity against HepG2 cell lines","volume":"23","author":"Eweas","year":"2014","journal-title":"Med. Chem. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/j.bmcl.2017.01.073","article-title":"New 1,4-dihydro [1,8] naphthyridine derivatives as DNA gyrase inhibitors","volume":"27","author":"Levent","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s12088-020-00910-6","article-title":"Potentiation of Antibiotic Activity by a Meldrum\u2019s Acid Arylamino Methylene Derivative against Multidrug-Resistant Bacterial Strains","volume":"61","author":"Freitas","year":"2021","journal-title":"Indian J. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"104268","DOI":"10.1016\/j.micpath.2020.104268","article-title":"Do 1,8-naphthyridine sulfonamides possess an inhibitory action against Tet (K) and MsrA efflux pumps in multiresistant Staphylococcus aureus strains?","volume":"147","author":"Tintino","year":"2020","journal-title":"Microb. Pathog."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Tintino, S.R., de Souza, V.C., Silva, J., Oliveira-Tintino, C.D.D.M., Pereira, P.S., Leal-Balbino, T.C., Pereira-Neves, A., Siqueira-Junior, J.P., da Costa, J.G., and Rodrigues, F.F. (2020). Effect of vitamin K3 inhibiting the function of NorA efflux pump and its gene expression on Staphylococcus aureus. Membranes, 10.","DOI":"10.3390\/membranes10060130"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.jgar.2020.11.027","article-title":"The 1,8-naphthyridines sulfonamides are NorA efflux pump inhibitors","volume":"24","author":"Muniz","year":"2021","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"105753","DOI":"10.1016\/j.ejps.2021.105753","article-title":"Chemical synthesis, molecular docking and MepA efflux pump inhibitory effect by 1,8-naphthyridines sulfonamides","volume":"160","author":"Tintino","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/ardp.201500237","article-title":"1,8-Naphthyridine Derivatives: A Review of Multiple Biological Activities","volume":"348","author":"Madaan","year":"2015","journal-title":"Arch. Pharmaz."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1248\/bpb.25.798","article-title":"Synthesis and pharmacological activities of 1,8-naphthyridine derivatives","volume":"25","author":"Leonard","year":"2002","journal-title":"Biol. Pharm. Bull."},{"key":"ref_37","first-page":"2412","article-title":"Identification of the potential biological target of N-benzenesulfonyl-1,2,3,4-tetrahydroquinoline compounds active against gram-positive and gram-negative bacteria","volume":"23","author":"Martinez","year":"2019","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_38","first-page":"98","article-title":"In vitro antimicrobial activity of Geraniol and Cariophyllene against Staphylococcus aureus","volume":"20","author":"Coutinho","year":"2015","journal-title":"Rev. Cuba. Plantas Med."},{"key":"ref_39","unstructured":"Brunton, L., Chabner, B., and Knollman, B. (2011). Goodman and Gilman\u2019s The Pharmacological Basis of Therapeutics, McGraw-Hill. [12th ed.]."},{"key":"ref_40","first-page":"1022","article-title":"Synthesis and antibacterial activity of a new derivative of the Meldrun acid: 2,2-dimethyl-5-(4H-1,2,4-triazol-4-ylaminomethylene)-1,3-dioxane-4,6-dione (C9H10N4O4)","volume":"13","author":"Sampaio","year":"2014","journal-title":"EXCLI J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.micpath.2017.12.058","article-title":"Evaluation of antibacterial and modifying action of catechin antibiotics in resistant strains","volume":"115","author":"Gomes","year":"2018","journal-title":"Microb. Pathog."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.micpath.2017.10.052","article-title":"Vanillin selectively modulates the action of antibiotics against resistant bacteria","volume":"113","author":"Bezerra","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.biopha.2017.06.020","article-title":"Evaluation of the antibacterial and modulatory potential of \u03b1-bisabolol, \u03b2-cyclodextrin and \u03b1-bisabolol\/\u03b2-cyclodextrin complex","volume":"92","author":"Pereira","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3107","DOI":"10.1021\/jm9509410","article-title":"De novo antimicrobial peptides with low mammalian cell toxicity","volume":"39","author":"Javadpour","year":"1996","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1159\/000151267","article-title":"Enhancement of the antibiotic activity against a multiresistant Escherichia coli by Mentha arvensis L. and chlorpromazine","volume":"54","author":"Coutinho","year":"2008","journal-title":"Chemotherapy"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/23\/7400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:40:21Z","timestamp":1760168421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/23\/7400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,6]]},"references-count":45,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["molecules26237400"],"URL":"https:\/\/doi.org\/10.3390\/molecules26237400","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2021,12,6]]}}}