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<\/h2>\n<\/h2>\nAntibiotic resistance is one of the greatest threats to human health facing the world today. The rise in multi-drug resistant bacterial pathogens threatens the vast medical advancements made possible by antibiotics over the last 70+ years. Surgery, premature infant care, cancer chemotherapy, care of the critically ill, and transplantation medicine to name a few fields are feasible only with the existence of effective antibiotic therapy. The Melander lab is currently pursing several approaches to tackling this problem.<\/p>\n
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One approach utilizes antibiotic adjuvants; small molecules that target resistance mechanisms and\u00a0 render bacteria susceptible to currently approved antibiotics.<\/p>\n
We use a phenotypic screening approach coupled with medicinal chemistry to identify and optimize\u00a0 compounds that mitigate acquired resistance to various antibiotic classes against a diverse spectrum of bacterial strains.<\/p>\n
We utilize a variety of biochemical and genetic methods to investigate the mechanisms of action of lead compounds including: pull-down assays with labelled compounds, screening of mutant libraries, quantification of RNA and protein expression levels, analysis of the composition of the bacterial cell wall and membrane, analysis of cell permeability and compound efflux, and analysis of enzymatic activity.<\/p>\n
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Melander, R.J. and Melander, C.<\/strong> The Challenge of Overcoming Antibiotic Resistance: An Adjuvant Approach. ACS Infectious Diseases<\/em>, 2017<\/strong>, 3, <\/em>559-563. <\/em>doi.org\/10.1021\/acsinfecdis.7b00071<\/a><\/span><\/p>\n Melander, R.J., and Melander, C. Antibiotic Adjuvants.\u00a0Topics in Medicinal Chemistry: Antibacterials (Springer)<\/em>.\u00a02017<\/strong>, 25, 89-118.\u00a0doi.org\/10.1007\/7355_2017_10<\/a><\/span><\/p>\n Bacteria acquire resistance to antibiotics through a number of mechanisms, these include: antibiotic modification, target modification, efflux, and decreased antibiotic uptake. Additionally the pathways that activate and regulate these resistance mechanisms represent a target for enhancing antibiotic activity.<\/p>\n <\/p>\n Examples of adjuvant mechanisms of action and discovery: (A) inhibition of antibiotic modification; (B) inhibition of target modification; (C) inhibition of efflux; (D) enhancement of antibiotic uptake; (E) inhibition of signaling pathways that mediate antibiotic resistance; (F) inhibition of biofilm formation, which leads to increased antibiotic tolerance; (G) target-blind whole cell screening of previously approved drugs for adjuvant activity.<\/span><\/p>\n <\/p>\n Applications for which we have identified active compounds include:<\/p>\n Brackett, C.M., Melander, R.J., An, I.H., Krisnamurthy, A., Thompson, R.J., Cavanagh, J., and Melander, C. Small Molecule Suppression of \u00df-Lactam Resistance in Multi-drug Resistant Gram-negative Pathogens.\u00a0Journal of Medicinal Chemistry,\u00a0<\/em>2014<\/strong>,\u00a057<\/em>\u00a0(17), 7450-7458.\u00a0<\/em>doi.org\/10.1021\/jm501050e<\/a><\/span><\/p>\n Harris, T.L., Worthington, R.J., and Melander, C. Potent Small Molecule Suppression of Oxacillin Resistance in methicillin-resistant\u00a0Staphylococcus aureus<\/em>.\u00a0Angewandte Chemie,\u00a0<\/em>2012<\/strong>,\u00a051<\/em>\u00a0(45), 11254-11257.\u00a0<\/em>doi.org\/10.1002\/anie.201206911<\/a><\/span><\/p>\n <\/p>\n Barker, W. T., Jania, L. A., Melander, R. J.,\u00a0 Koller, B. H., and Melander, C. Eukaryotic Phosphatase Inhibitors Enhance Colistin Efficacy in Gram-negative Bacteria.\u00a0Chemical Biology & Drug Design.\u00a0doi.org\/10.1111\/cbdd.13735<\/a><\/em><\/span><\/p>\n Nemeth, A. M., Basak, A. K., Weig, A. W., Marrujo, S. A., Barker, W. T., Jania, L. A., Hendricks, T. A., Sullivan, A. E., O\u2019Connor, P. M., Melander, R. J., Koller, B. H., and Melander. C. Structure Function Studies on IMD-0354 Identifies Highly Active Colistin Adjuvants. ChemMedChem.\u00a0<\/em>2020<\/strong>, 15 (2) 210-218\u00a0doi.org\/10.1002\/cmdc.201900560<\/a><\/span><\/p>\n Barker, W. T., Nemeth, A. M., Brackett, S. M., Basak, A. K., Chandler, C. E., Jania, L. A., Zuercher, W. J., Melander, R. J., Koller, B. H., Ernst, R. K. and Melander, C. Repurposing Eukaryotic Kinase Inhibitors as Colistin Adjuvants in Gram-negative Bacteria. ACS Infectious Diseases,\u00a0<\/em>2019<\/span><\/strong>,\u00a0<\/span><\/em>5<\/span>,\u00a0<\/span><\/em>(10),\u00a0<\/span>1764-1771\u00a0<\/span>doi.org\/10.1021\/acsinfecdis.9b00212<\/a><\/span><\/p>\n <\/p>\n Another application is expanding the spectrum of currently used antibiotics by overcoming intrinsic resistance mechanisms.<\/p>\n Examples include:<\/p>\n Martin, S.E., Melander, R.J., Brackett, C.M., Scott, A.J., Chandler, C.E., Nguyen, C.M., Minrovic, B.M., Harrill, S.E., Ernst. R.K., Manoil, C., and Melander, C. Small Molecule Potentiation of Gram-positive Selective Antibiotics Against\u00a0Acinetobacter baumannii<\/em>.\u00a0ACS Infectious Diseases,\u00a0<\/em>2019<\/strong>, 5, (7), 1223-1230\u00a0doi.org\/10.1021\/acsinfecdis.9b00067<\/a><\/span><\/p>\n Hubble, V.B., Hubbard, B., Minrovic, B.M., Melander, R.J., and Melander, C. Using Small Molecule Adjuvants to Repurpose Azithromycin for Use Against\u00a0Pseudomonas aeruginosa<\/em>.\u00a0ACS Infectious Diseases,\u00a0<\/em>2019<\/strong>,\u00a0<\/em>5 (1), 141-151.\u00a0doi.org\/10.1021\/acsinfecdis.8b00288<\/a><\/span><\/p>\n <\/p>\n Nguyen, T.V., Blackledge, M.S., Lindsey, E.A., Minrovic, B.M., Ackart, D.F., Jeon, A.B., Obregon-Henao, A., Melander, R.J., Basaraba, R.J., and Melander, C. The Discovery of 2-Aminobenzimidazoles that Sensitize\u00a0M. smegmatis\u00a0<\/em>and\u00a0M. tuberculosis\u00a0<\/em>to \u00df-Lactam Antibiotics in a Pattern Distinct from \u00df-Lactamase Inhibitors.\u00a0Angewandte Chemie,\u00a0<\/em>2017<\/strong>,\u00a056<\/em>\u00a0(14), 3940-3944.\u00a0<\/em>doi.org\/10.1002\/anie.201612006<\/a><\/span><\/p>\n Jeon, A.B., Obregon-Henao, A., Ackart, D.F., Podell, B.K., Belardinelli, J., Jackson, M., Nguyen, T.V., Blackledge, M.S., Melander, R.J., Melander, C., Johnson, B., Abramovitch, R., and Basaraba, R.J. 2-Aminoimidazoles Potentiate \u00df-Lactam Antimicrobial Activity against\u00a0Mycobacterium tuberculosis<\/em>\u00a0by Reducing \u00df-Lactamase Secretion and Increasing Cell Wall Permeability.\u00a0PLOS One<\/em>,\u00a02017<\/strong>,\u00a012,\u00a0<\/em>e0180925.\u00a0<\/em>doi.org\/10.1371\/journal.pone.0180925<\/a><\/span><\/p>\n <\/p>\n We are also investigating compounds that further enhance the sensitivity of antibiotics against susceptible strains. This has the potential to enable lower antibiotic dosing, which would lead to\u00a0 a reduction in unwanted side effects and potentially reduced rates of resistance evolution.<\/p>\n Minrovic, B.M., Jung, D., Melander, R.J., and Melander, C. A New Class of Adjuvants Enables Lower Dosing of Colistin Against\u00a0Acinetobacter baumanii<\/em>.\u00a0ACS Infectious Diseases,\u00a0<\/em>2018<\/strong>,\u00a04\u00a0<\/em>(9),\u00a0<\/em>1368-1376.\u00a0<\/em>doi.org\/10.1021\/acsinfecdis.8b00103<\/a><\/span><\/p>\n <\/p>\n In addition to genotypic antibiotic resistance mechanisms, bacterial tolerance is another phenomenon for which adjuvants can be utilized. Bacteria can exhibit phenotypes that impart increased tolerance to both antibiotics and host immune responses. Examples of such phenotypes include the adoption of a persister state, and the formation of biofilms.<\/p>\n Biofilms are defined as a surface attached community of bacteria encased in an extracellular matrix. Bacteria within a biofilm are typically 100-1000-fold more resistant to antibiotics than planktonic bacteria,and are recalcitrant to clearance by the host immune response.<\/p>\n Anti-biofilm agents have the potential to enhance the efficacy of antibiotics for the treatment of numerous infections including: infections of IMD, chronic wound infections and lung infections in cystic fibrosis patients.<\/p>\n Melander, R.J., and Melander, C. Strategies for the Eradication of Biofilm-Based Bacterial Infections. Antibacterial Drug Discovery to Combat MDR. (Springer)<\/em>\u00a02019<\/strong>, 499-526\u00a0doi.org\/10.1007\/978-981-13-9871-1_22<\/a><\/span><\/p>\n Melander, R. J., Basak, A. K., and Melander, C. Natural Products as Inspiration for the Development of Bacterial Antibiofilm Agents.\u00a0Natural Product Reports.\u00a0<\/em>doi.org\/10.1039\/D0NP00022A<\/a><\/span><\/p>\n <\/p>\n To address this problem, we are investigating the effects that simple structural motifs found embedded in complex marine natural products have upon biofilm development and maintenance. We have demonstrated that simple derivatives of marine alkaloid natural products inhibit and disperse biofilms from pathogenic Gram-negative, Gram-positive, and mycobacteria as well as fungi, and mixed species biofilms.<\/p>\n <\/p>\n Brackett, S. M.,\u00a0 Cox, K. E.,\u00a0 Barlock, S. L.,\u00a0 Huggins, W. M.,\u00a0 Ackart, D. F.,\u00a0 Bassaraba, R. J.,\u00a0 Melander, R. J., and Melander, C. Meridianin D Analogues Possess Antibiofilm Activity Against\u00a0Mycobacterium smegmatis. RSC Medicinal Chemistry.\u00a0<\/em>2020<\/strong>, 11, 92-97\u00a0doi.org\/10.1039\/C9MD00466A<\/a><\/span><\/p>\n Huggins, W.M., Nguyen, T.V., Hahn, N.A., Baker, J.T., Kuo, L.G., Kaur, D., Melander, R.J., Gunn, J.S., and Melander, C. 2-Aminobenzimidazoles as Antibiofilm Agents Against\u00a0Salmonella eterica\u00a0<\/em>Serovar Typhimurium.\u00a0MedChemComm,\u00a0<\/em>2018<\/strong>,\u00a09\u00a0<\/em>(9),\u00a0<\/em>1547-1522.\u00a0doi.org\/10.1039\/c8md00298c<\/a><\/span><\/p>\n Huggins, W.M., Barker, W.T., Baker, J.T., Hahn, N., Melander, R.J., and Melander, C. Meridianin D Analogues Display Antibiofilm Activity Against MRSA and Increase Colistin Efficacy in Gram-Negative Bacteria.\u00a0ACS Medicinal Chemistry Letters,\u00a0<\/em>2018<\/strong>,\u00a09\u00a0<\/em>(7),\u00a0<\/em>702-707\u00a0doi.org\/10.1021\/acsmedchemlett.8b00161<\/a><\/span><\/p>\n <\/p>\n <\/p>\n Another avenue we are pursuing focuses on developing that possess narrow spectrum antibiotic profiles,\u00a0 and thus potentially less damaging to commensal flora, and less susceptible to resistance evolution.<\/p>\n Melander, R.J., Zurawski, D.V., and Melander, C. Narrow-Spectrum Antibacterial Agents.\u00a0 MedChemComm, <\/em>2018<\/strong>, 9, <\/em>12-21. <\/em>doi.org\/10.1039\/C7MD00528H<\/a><\/span><\/p>\n <\/p>\n <\/p>\n <\/p>\n \n Huggins. W.M., Minrovic, B.M., Corey, B.W., Jacobs, A.C., Melander, R.J., Zurawski, D.V., and Melander, C. 1,2,4-Triazolidine-3-thiones as Narrow Spectrum Antibiotics Against Multi-Drug Resistant\u00a0Acinetobacter baumannii<\/em>.\u00a0ACS Medicinal Chemistry Letters,\u00a0<\/em>2017<\/strong>,\u00a08\u00a0<\/em>(1), 27-31.\u00a0<\/em>doi.org\/10.1021\/acsmedchemlett.6b00296\u00a0<\/a><\/span><\/p>\n <\/p>\n John Cavanagh – East Carolina University<\/p>\n Robert Ernst – University of Maryland, Baltimore<\/p>\n Colin Manoil – University of Washington<\/p>\n Randall Basaraba – Colorado State University<\/p>\n Beverly Koller – University of North Carolina\u00a0 at Chapel Hill<\/p>\n Hui Wu – Oregon Health & Science University<\/p>\n Cassandra Quave – Emory University<\/p>\n John Gunn – The Ohio State University<\/p>\n Alex Horswill – University of Colorado School of Medicine<\/p>\n <\/p>\n","protected":false},"excerpt":{"rendered":" Multidrug Resistant Bacterial Pathogens Antibiotic resistance is one of the greatest threats to human health facing the world today. The rise in multi-drug resistant bacterial pathogens threatens the vast medical advancements made possible by antibiotics over the last 70+ years. Surgery, premature infant care, cancer chemotherapy, care of the critically ill, and transplantation medicine to … Continue reading “Research”<\/span><\/a><\/p>\n","protected":false},"author":3360,"featured_media":0,"parent":0,"menu_order":1,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-16","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/pages\/16","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/users\/3360"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/comments?post=16"}],"version-history":[{"count":45,"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/pages\/16\/revisions"}],"predecessor-version":[{"id":474,"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/pages\/16\/revisions\/474"}],"wp:attachment":[{"href":"https:\/\/sites.nd.edu\/melanderlab\/wp-json\/wp\/v2\/media?parent=16"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}<\/h4>\n
Reversing Acquired Resistance<\/h4>\n
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Expanding the Spectrum of Known Antibiotics<\/h4>\n
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Suppressing antibiotic tolerance<\/h4>\n
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<\/p>\nNarrow Spectrum Antibiotics<\/h3>\n
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<\/p>\nCollaborators<\/h2>\n