{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T10:48:48Z","timestamp":1776509328635,"version":"3.51.2"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020560","name":"Universidad Santiago de Cali","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020560","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p>Antimicrobial resistance is a significant public health concern worldwide. Currently, infections by antibiotic-resistant Gram-negative and Gram-positive bacteria are managed using the lipopeptide antibiotics colistin and daptomycin, which target the microbial membrane. Despite the fact that both are short, cyclic, and have a common acylated group, they display remarkable antimicrobial selectivity. Colistin exhibits activity only against gram-negative bacteria, while daptomycin only against gram-positive bacteria. However, the mechanism behind this selectivity is unclear. Here, we performed molecular dynamics simulations to study the interactions between <jats:italic>Escherichia coli<\/jats:italic> membrane models composed of 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoethanolamine (POPE)\/1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoglycerol (POPG) with daptomycin and colistin, independently. Similarly, we simulated the interaction between the <jats:italic>Staphyloccocus aureus<\/jats:italic> model membrane composed of POPG and cardiolipin (PMCL1) with both antibiotics. We observed that colistin interacted via hydrogen bonds and electrostatic interactions with the polar head of POPE in <jats:italic>E. coli<\/jats:italic> membrane models, mediated by 2,4-diaminobutyric acid (DAB) residues, which facilitated the insertion of its acyl tail into the hydrophobic core of the bilayer. In <jats:italic>S. aureus<\/jats:italic> membrane models, weaker interactions were observed with the polar head, particularly POPG, which was insufficient for the insertion of the lipid tail into the membrane. However, daptomycin displayed strong interactions with several POPG functional groups of the <jats:italic>S. aureus<\/jats:italic> membrane model, which favored the insertion of the fatty acid tail into the bilayer. Contrastingly, daptomycin showed negligible interactions with the <jats:italic>E. coli<\/jats:italic> membrane, except for the amino group of the POPE polar head, which might repel the calcium ions conjugated with the lipopeptide. Based on these results, we identified key amino acid-phospholipid interactions that likely contribute to this antibacterial selectivity, which might contribute to designing and developing future antimicrobial peptides.<\/jats:p>","DOI":"10.3389\/fbinf.2025.1569480","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:24:48Z","timestamp":1752729888000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Understanding the selectivity in silico of colistin and daptomycin toward gram-negative and gram-positive bacteria, respectively, from the interaction with membrane phospholipids"],"prefix":"10.3389","volume":"5","author":[{"given":"Yesid","family":"Aristizabal","sequence":"first","affiliation":[]},{"given":"Yamil","family":"Liscano","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9","family":"O\u00f1ate-Garz\u00f3n","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"Gromacs: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"449","DOI":"10.3390\/membranes11060449","article-title":"A study of the interaction of a new benzimidazole schiff base with synthetic and simulated membrane models of bacterial and mammalian membranes","volume":"11","author":"Arag\u00f3n-Muriel","year":"2021","journal-title":"Membranes"},{"key":"B3","doi-asserted-by":"publisher","first-page":"6983","DOI":"10.1128\/AAC.01303-15","article-title":"Stepwise decrease in daptomycin susceptibility in clinical staphylococcus aureus isolates associated with an initial mutation in rpoB and a Compensatory Inactivation of the clpX Gene","volume":"59","author":"B\u00e6k","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1039\/b402722a","article-title":"NMR structure determination and calcium binding effects of lipopeptide antibiotic daptomycin","volume":"2","author":"Ball","year":"2004","journal-title":"Org. Biomol. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00232-019-00067-4","article-title":"Role of lipid composition, physicochemical interactions, and membrane mechanics in the molecular actions of microbial cyclic lipopeptides","volume":"252","author":"Balleza","year":"2019","journal-title":"J. Membr. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.cbpa.2009.02.031","article-title":"Daptomycin: mechanisms of action and resistance, and biosynthetic engineering","volume":"13","author":"Baltz","year":"2009","journal-title":"Curr. Opin. Chem. Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e1004180","DOI":"10.1371\/journal.pcbi.1004180","article-title":"Interaction of the antimicrobial peptide polymyxin B1 with both membranes of E. coli: a molecular dynamics study","volume":"11","author":"Berglund","year":"2015","journal-title":"PLoS Comput. Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1185\/03007995.2015.1018989","article-title":"Colistin, mechanisms and prevalence of resistance","volume":"31","author":"Bialvaei","year":"2015","journal-title":"Curr. Med. Res. Opin."},{"key":"B10","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.peptides.2012.12.002","article-title":"Quorum sensing inhibitor FS3-coated vascular graft enhances daptomycin efficacy in a rat model of staphylococcal infection","volume":"40","author":"Cirioni","year":"2013","journal-title":"Peptides"},{"key":"B11","doi-asserted-by":"publisher","first-page":"105271","DOI":"10.1016\/j.envint.2019.105271","article-title":"Environmental fate processes of antimicrobial peptides daptomycin, bacitracins, and polymyxins","volume":"134","author":"Davis","year":"2020","journal-title":"Environ. Int."},{"key":"B12","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/j.bpj.2017.12.027","article-title":"Selective interaction of colistin with lipid model membranes","volume":"114","author":"Dupuy","year":"2018","journal-title":"Biophysical J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.febslet.2005.11.064","article-title":"Molecular dynamics simulation of a phosphatidylglycerol membrane","volume":"580","author":"Elmore","year":"2006","journal-title":"FEBS Lett."},{"key":"B14","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1080\/22221751.2020.1754133","article-title":"Colistin and its role in the Era of antibiotic resistance: an extended review (2000\u20132019)","volume":"9","author":"El-Sayed Ahmed","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1086\/429323","article-title":"Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections","volume":"40","author":"Falagas","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1128\/AAC.00039-06","article-title":"Genetic changes that correlate with reduced susceptibility to daptomycin in Staphylococcus aureus","volume":"50","author":"Friedman","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"B17","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/s43586-022-00184-w","article-title":"Principal component analysis","volume":"2","author":"Greenacre","year":"2022","journal-title":"Nat. Rev. Methods Prim."},{"key":"B18","doi-asserted-by":"publisher","first-page":"17025","DOI":"10.1021\/ja045455t","article-title":"Synthesis and derivatization of daptomycin: a chemoenzymatic route to acidic lipopeptide antibiotics","volume":"126","author":"Gr\u00fcnewald","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2371","DOI":"10.1021\/ct900275y","article-title":"An implementation of the smooth particle mesh Ewald method on GPU hardware","volume":"5","author":"Harvey","year":"2009","journal-title":"J. Chem. Theory Comput."},{"key":"B20","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.bpc.2018.04.001","article-title":"Biophysical evaluation of cardiolipin content as a regulator of the membrane lytic effect of antimicrobial peptides","volume":"238","author":"Hern\u00e1ndez-Villa","year":"2018","journal-title":"Biophys. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/s00249-007-0227-2","article-title":"Effect of divalent cations on the structure of the antibiotic daptomycin","volume":"37","author":"Ho","year":"2008","journal-title":"Eur. Biophys. J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1093\/jac\/dkn321","article-title":"Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus","volume":"62","author":"Hobbs","year":"2008","journal-title":"J. Antimicrob. Chemother."},{"key":"B23","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1093\/oxfordjournals.jbchem.a021226","article-title":"Structure determination of an immunopotentiator peptide, cinnamycin, complexed with lysophosphatidylethanolamine by 1H-NMR","volume":"119","author":"Hosoda","year":"1996","journal-title":"J. Biochem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"6615","DOI":"10.1021\/la504049q","article-title":"Investigating hydrophilic pores in model lipid bilayers using molecular simulations: correlating bilayer properties with pore-formation thermodynamics","volume":"31","author":"Hu","year":"2015","journal-title":"Langmuir"},{"key":"B25","doi-asserted-by":"publisher","first-page":"183395","DOI":"10.1016\/j.bbamem.2020.183395","article-title":"DAPTOMYCIN, its membrane-active mechanism vs. that of other antimicrobial peptides","volume":"1862","author":"Huang","year":"2020","journal-title":"Biochimica Biophysica Acta - Biomembr."},{"key":"B26","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1080\/10618600.1996.10474713","article-title":"R: a language for data analysis and graphics","volume":"5","author":"Ihaka","year":"1996","journal-title":"J. Comput. Graph. Statistics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/j.chembiol.2004.04.020","article-title":"Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin","volume":"11","author":"Jung","year":"2004","journal-title":"Chem. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.ijantimicag.2017.01.005","article-title":"Effects of colistin on biofilm matrices of Escherichia coli and Staphylococcus aureus","volume":"49","author":"Klinger-Strobel","year":"2017","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B29","volume-title":"Lipodepsipeptide antibiotics: total synthesis and mechanism of action studies using 19F-NMR","author":"Kralt","year":"2020"},{"key":"B30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-03243-2_649-1","article-title":"Principal component analysis (PCA)","volume-title":"Computer vision","author":"Kurita","year":"2020"},{"key":"B31","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.tifs.2021.01.005","article-title":"The structure-mechanism relationship and mode of actions of antimicrobial peptides: a review","volume":"109","author":"Li","year":"2021","journal-title":"Trends Food Sci. Technol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"238","DOI":"10.3390\/antibiotics8040238","article-title":"Increases in hydrophilicity and charge on the polar face of alyteserin 1c helix change its selectivity towards gram-positive bacteria","volume":"8","author":"Liscano","year":"2019","journal-title":"Antibiotics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1128\/AAC.45.3.845-851.2001","article-title":"Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection","volume":"45","author":"Louie","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"B34","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.jmb.2008.10.018","article-title":"Principal component analysis for protein folding dynamics","volume":"385","author":"Maisuradze","year":"2009","journal-title":"J. Mol. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1111\/j.1365-2958.2006.05317.x","article-title":"Lipid domains in bacterial membranes","volume":"61","author":"Matsumoto","year":"2006","journal-title":"Mol. Microbiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1002\/jms.3233","article-title":"The ornithine effect in peptide cation dissociation","volume":"48","author":"McGee","year":"2013","journal-title":"J. Mass Spectrom."},{"key":"B37","doi-asserted-by":"publisher","first-page":"4494","DOI":"10.1128\/JB.00011-12","article-title":"Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins","volume":"194","author":"Pogliano","year":"2012","journal-title":"J. Bacteriol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s00232-021-00175-0","article-title":"The antibiotic peptide daptomycin functions by reorganizing the membrane","volume":"254","author":"Pokorny","year":"2021","journal-title":"J. Membr. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1128\/AAC.02005-12","article-title":"The target of daptomycin is absent from Escherichia coli and other gram-negative pathogens","volume":"57","author":"Randall","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2701","DOI":"10.1002\/1873-3468.14206","article-title":"Cardiolipin prevents pore formation in phosphatidylglycerol bacterial membrane models","volume":"595","author":"Rocha\u2010Roa","year":"2021","journal-title":"FEBS Lett."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e65836","DOI":"10.7554\/eLife.65836","article-title":"Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane","volume":"10","author":"Sabnis","year":"2021","journal-title":"eLife"},{"key":"B42","first-page":"329","article-title":"Applications of BIOVIA materials studio, LAMMPS, and GROMACS in various fields of science and engineering","volume-title":"Molecular dynamics simulation of nanocomposites using BIOVIA materials Studio","author":"Sharma","year":"2019"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1128\/AAC.47.8.2538-2544.2003","article-title":"Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus","volume":"47","author":"Silverman","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e1601017","DOI":"10.1126\/sciadv.1601017","article-title":"Polymyxins and quinazolines are LSD1\/KDM1A inhibitors with unusual structural features","volume":"2","author":"Speranzini","year":"2016","journal-title":"Sci. Adv."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/j.bbamem.2006.02.009","article-title":"Mode of action of the new antibiotic for Gram-positive pathogens daptomycin: comparison with cationic antimicrobial peptides and lipopeptides","volume":"1758","author":"Straus","year":"2006","journal-title":"Biochimica Biophysica Acta - Biomembr."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.5455\/njppp.2019.9.0620508062019","article-title":"Self-medication: is a serious challenge to control antibiotic resistance?","author":"Sunny","year":"2019","journal-title":"Natl. J. Physiology, Pharm. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"6253","DOI":"10.1016\/j.bmc.2016.05.052","article-title":"The action mechanism of daptomycin","volume":"24","author":"Taylor","year":"2016","journal-title":"Bioorg. and Med. Chem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.cis.2017.06.001","article-title":"The interaction of antimicrobial peptides with membranes","volume":"247","author":"Travkova","year":"2017","journal-title":"Adv. Colloid Interface Sci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"a025288","DOI":"10.1101\/cshperspect.a025288","article-title":"Polymyxin: alternative mechanisms of action and resistance","volume":"6","author":"Trimble","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"18889","DOI":"10.1021\/acsomega.9b02949","article-title":"Structure and dynamics of cinnamycin-lipid complexes: mechanisms of selectivity for phosphatidylethanolamine lipids","volume":"4","author":"Vestergaard","year":"2019","journal-title":"ACS Omega"},{"key":"B51","doi-asserted-by":"publisher","first-page":"18363","DOI":"10.1021\/acsami.0c02752","article-title":"Structural superiority of guanidinium-rich, four-armed copolypeptides: role of multiple peptide-membrane interactions in enhancing bacterial membrane perturbation and permeability","volume":"12","author":"Wang","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1298","article-title":"Using PyMOL as a platform for computational drug design","volume":"7","author":"Yuan","year":"2017","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1021\/acsinfecdis.6b00152","article-title":"Daptomycin leakage is selective","volume":"2","author":"Zhang","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1016\/j.bbapap.2017.07.020","article-title":"On the quest for the elusive mechanism of action of daptomycin: binding, fusion, and oligomerization","volume":"1865","author":"Zhang","year":"2017","journal-title":"Biochimica Biophysica Acta (BBA) - Proteins Proteomics"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.3390\/ijms19041186","article-title":"Molecular dynamics simulations of human antimicrobial peptide LL-37 in model POPC and POPG lipid bilayers","volume":"19","author":"Zhao","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/j.biochi.2008.02.025","article-title":"Role of phosphatidylglycerols in the stability of bacterial membranes","volume":"90","author":"Zhao","year":"2008","journal-title":"Biochimie"}],"container-title":["Frontiers in Bioinformatics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2025.1569480\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:24:50Z","timestamp":1752729890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2025.1569480\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":56,"alternative-id":["10.3389\/fbinf.2025.1569480"],"URL":"https:\/\/doi.org\/10.3389\/fbinf.2025.1569480","relation":{},"ISSN":["2673-7647"],"issn-type":[{"value":"2673-7647","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,17]]},"article-number":"1569480"}}