{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:43:04Z","timestamp":1760233384986,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T00:00:00Z","timestamp":1610496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["PHS GM100962"],"award-info":[{"award-number":["PHS GM100962"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule\u2019s tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a \u201ctaming\u201d strategy), we found that by covalently attaching one or more facial amphiphiles (\u201cfloats\u201d) to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such \u201cmonomer control\u201d and \u201ctaming\u201d strategies to other membrane-disrupting antimicrobial agents is briefly discussed.<\/jats:p>","DOI":"10.3390\/molecules26020374","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T11:52:32Z","timestamp":1610538752000},"page":"374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming"],"prefix":"10.3390","volume":"26","author":[{"given":"Steven L.","family":"Regen","sequence":"first","affiliation":[{"name":"Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,13]]},"reference":[{"key":"ref_1","unstructured":"(2020, December 20). Antimicrobial Threats Report by the Center of Disease Control and Prevention (CDC), Available online: https:\/\/www.cdc.gov\/drugresistance\/pdf\/threats-report\/2019-ar-threats-report-508.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1021\/acs.bioconjchem.0c00323","article-title":"Comprehensive review on current interventions, diagnostics and nanotechnology perspectives against SARS-CoV-2","volume":"31","author":"Chauhan","year":"2020","journal-title":"Bioconj. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.4103\/ijp.IJP_115_20","article-title":"Drug targets for coronaviruses: A systematic review","volume":"52","author":"Prajapat","year":"2020","journal-title":"Indian J. Pharmacol."},{"key":"ref_4","first-page":"161","article-title":"Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: A possible strategy for reducing SARS-CoV-2 infectivity","volume":"91","author":"Baglivo","year":"2020","journal-title":"Acta Biomed."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1021\/acsinfecdis.0c00331","article-title":"Antibiotics special issue: Challenges and opportunities in antibiotic discovery","volume":"6","author":"Blaskovich","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1021\/acsinfecdis.0c00044","article-title":"The antibacterial research and development pipeline needs urgent solutions","volume":"6","author":"Beyer","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1021\/acsinfecdis.0c00100","article-title":"On the road to discovering urgently needed antibiotics: So close yet so far away","volume":"6","author":"Kim","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1021\/acsinfecdis.0c00057","article-title":"Antibacterial drugs: The last frontier","volume":"6","author":"Shlaes","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1021\/acsinfecdis.0c00026","article-title":"Innovation in antimicrobial resistance: The CARB-X perspective","volume":"6","author":"Alm","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1021\/acsinfecdis.0c00001","article-title":"Multitarget approaches against multiresistant superbugs","volume":"6","author":"Gray","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e02057-19","DOI":"10.1128\/AAC.02057-19","article-title":"The economic conundrum for antibacterial drugs","volume":"64","author":"Shlaes","year":"2020","journal-title":"Anitimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1039\/C5MD00389J","article-title":"Mechanisms of resistance to membrane-disrupting antibiotics in Gram-positive and Gram-negative bacteria","volume":"7","author":"Steinbuch","year":"2016","journal-title":"Med. Chem. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1086\/649858","article-title":"Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america","volume":"50","author":"Perfect","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1128\/AAC.02681-15","article-title":"Cell wall changes in amphotericin b-resistant strains from candida tropicalis and relationship with the immune responses elicited by the host","volume":"60","author":"Rueda","year":"2016","journal-title":"Anitimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1021\/acs.biochem.9b00180","article-title":"The perpendicular orientation of amphotericin b methyl ester in hydrated lipid bilayers supports the barrel-stave model","volume":"58","author":"Yamamoto","year":"2019","journal-title":"Biochemistry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/0005-2736(78)90276-6","article-title":"Effect of amphotericin b on cholesterol-containing liposomes of egg phosphatidylcholine and didocosenoyl phosphatidylcholine: A refinement of the model for the formation of pores by amphotericin b in membranes","volume":"511","year":"1978","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00249-014-0983-8","article-title":"Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments","volume":"43","author":"Kaminski","year":"2014","journal-title":"Eur. Biophys. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1128\/AAC.00270-13","article-title":"Structure-antifungal activity relationships of polyene antibiotics of the amphotericin b group","volume":"57","author":"Tevyashova","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1039\/b820743g","article-title":"Synthesis and biological evaluation of amphotericin B derivatives","volume":"27","author":"Volmer","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/myc.12283","article-title":"Comparison of nephrotoxicity associated to different lipid formulations of amphotericin b: A real-life study","volume":"58","author":"Falci","year":"2015","journal-title":"Mycoses"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nchembio.1821","article-title":"Nontoxic antimicrobials that evade drug resistance","volume":"11","author":"Davis","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8488","DOI":"10.1021\/ja403255s","article-title":"C2\u2019OH of Amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells","volume":"135","author":"Wilcock","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nchembio.1496","article-title":"Amphotericin forms an extramembranous and fungicidal sterol sponge","volume":"10","author":"Anderson","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1128\/AAC.36.11.2518","article-title":"Effects of aggregation and solvent on the toxicity of amphotericin b to human erythrocytes","volume":"36","author":"Legrand","year":"1992","journal-title":"Anitimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"361","DOI":"10.2165\/00003495-200969030-00010","article-title":"Liposomal amphotericin B: A review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections","volume":"69","author":"Moen","year":"2009","journal-title":"Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1021\/ja00055a047","article-title":"Control over vesicle rupture and leakage by membrane packing and by the aggregation state of an attacking surfactant","volume":"115","author":"Liu","year":"1993","journal-title":"J. Am. Chem. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6249","DOI":"10.1021\/ja00128a011","article-title":"Micelle\/monomer control over the membrane-disrupting properties of an amphiphilic antibiotic","volume":"117","author":"Yamashita","year":"1995","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1021\/acs.bioconjchem.5b00463","article-title":"Taming amphotericin b","volume":"26","author":"Janout","year":"2015","journal-title":"Bioconjugate Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2850","DOI":"10.1021\/acs.bioconjchem.6b00629","article-title":"A simple strategy for taming membrane-disrupting antibiotics","volume":"27","author":"Yu","year":"2016","journal-title":"Bioconjugate Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10886","DOI":"10.1021\/bi00034a023","article-title":"Bile acid\/phosphatidylcholine interactions in mixed monomolecular layers: Differences in condensation effects but not interfacial orientation between hydrophobic and hydrophilic bile acid species","volume":"34","author":"Fahey","year":"1995","journal-title":"Biochemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13771","DOI":"10.1021\/ja804929m","article-title":"Viewing membrane-bound molecular umbrellas by parallax analyses","volume":"130","author":"Kondo","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3389\/fcimb.2019.00128","article-title":"Application of antimicrobial peptides of the innate immune system in combination with conventional antibiotics: A novel way to combat antibiotic resistance","volume":"9","author":"Zharkova","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_33","first-page":"3919","article-title":"The antimicrobial peptides and their potential clinical applications","volume":"11","author":"Lei","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3389\/fcimb.2016.00194","article-title":"Antimicrobial peptides: An emerging category of therapeutic agents","volume":"6","author":"Mahlapuu","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1080\/02713680590968637","article-title":"A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs","volume":"30","author":"Gordon","year":"2005","journal-title":"Curr. Eye. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.tips.2017.01.003","article-title":"Cell-penetrating peptides: From basic research to clinics","volume":"38","author":"Guidotti","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3389\/fphar.2020.00697","article-title":"Cell-penetrating peptides in diagnosis and treatment of human diseases: From preclinical research to clinical application","volume":"11","author":"Xie","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20061100","article-title":"Cell-penetrating peptides and antimicrobial peptides: How different are they?","volume":"399","author":"Henriques","year":"2006","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1016\/j.peptides.2006.01.006","article-title":"Quantitatively determined uptake of cell-penetrating peptides in non-mammalian cells with an evaluation of degradation and antimicrobial effects","volume":"27","author":"Palm","year":"2006","journal-title":"Peptides"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1021\/acsinfecdis.5b00047","article-title":"Quaternary ammonium compounds: An antimicrobial mainstay and platform for innovation to address bacterial resistance","volume":"1","author":"Jennings","year":"2015","journal-title":"ACS Infect. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.bioorg.2015.01.001","article-title":"Synthesis, micellization and interaction of novel quaternary ammonium compounds derived from L-phenylalanine with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine as model membrane in relation to their antibacterial activity, and their selectivity over human red blood cells","volume":"58","author":"Joondan","year":"2015","journal-title":"Bioorg. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1021\/acsinfecdis.0c00037","article-title":"Broadening activity of polylmyxin by quaternary ammonium grafting","volume":"6","author":"Ongwae","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1021\/acs.accounts.0c00569","article-title":"Maxamycins: Durable antibiotics derived by rational redesign of vancomycin","volume":"53","author":"Wu","year":"2020","journal-title":"Acc. Chem. Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/2\/374\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:10:27Z","timestamp":1760159427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/2\/374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,13]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["molecules26020374"],"URL":"https:\/\/doi.org\/10.3390\/molecules26020374","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2021,1,13]]}}}