Abstract
A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant ‘persister’ subpopulations that exhibit high levels of tolerance to antibiotics1,2,3 and have a role in chronic or recurrent infections4,5. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans–MRSA infection screen6 to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
Nature Communications Open Access 14 November 2022
-
Antibacterial metal nanoclusters
Journal of Nanobiotechnology Open Access 16 July 2022
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Get just this article for as long as you need it
$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Allison, K. R., Brynildsen, M. P. & Collins, J. J. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473, 216–220 (2011)
Conlon, B. P. et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365–370 (2013)
Davies, J. & Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74, 417–433 (2010)
Lew, D. P. & Waldvogel, F. A. Osteomyelitis. Lancet 364, 369–379 (2004)
Baddour, L. M. et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 132, 1435–1486 (2015)
Rajamuthiah, R. et al. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus. PLoS ONE 9, e89189 (2014)
Altucci, L., Leibowitz, M. D., Ogilvie, K. M., de Lera, A. R. & Gronemeyer, H. RAR and RXR modulation in cancer and metabolic disease. Nat. Rev. Drug Discov. 6, 793–810 (2007)
Valli, C. et al. Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity. Mol. Cancer Ther. 7, 2941–2954 (2008)
Tang, X.-H. et al. Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. Proc. Natl Acad. Sci. USA 111, 8907–8912 (2014)
Han, T. et al. The antitumor toxin CD437 is a direct inhibitor of DNA polymerase α. Nat. Chem. Biol. 12, 511–515 (2016)
Irby, C. E., Yentzer, B. A. & Feldman, S. R. A review of adapalene in the treatment of acne vulgaris. J. Adolesc. Health 43, 421–424 (2008)
Meehl, M., Herbert, S., Götz, F. & Cheung, A. Interaction of the GraRS two-component system with the VraFG ABC transporter to support vancomycin-intermediate resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 51, 2679–2689 (2007)
Yang, S.-J. et al. The Staphylococcus aureus two-component regulatory system, GraRS, senses and confers resistance to selected cationic antimicrobial peptides. Infect. Immun. 80, 74–81 (2012)
Elbaz, M. & Ben-Yehuda, S. The metabolic enzyme ManA reveals a link between cell wall integrity and chromosome morphology. PLoS Genet. 6, e1001119 (2010)
Falord, M., Mäder, U., Hiron, A., Débarbouillé, M. & Msadek, T. Investigation of the Staphylococcus aureus GraSR regulon reveals novel links to virulence, stress response and cell wall signal transduction pathways. PLoS ONE 6, e21323 (2011)
Göhring, N. et al. New role of the disulfide stress effector YjbH in β-lactam susceptibility of Staphylococcus aureus. Antimicrob. Agents Chemother. 55, 5452–5458 (2011)
Friedrich, C. L., Moyles, D., Beveridge, T. J. & Hancock, R. E. Antibacterial action of structurally diverse cationic peptides on gram-positive bacteria. Antimicrob. Agents Chemother. 44, 2086–2092 (2000)
Chen, Y.-F., Sun, T.-L., Sun, Y. & Huang, H. W. Interaction of daptomycin with lipid bilayers: a lipid extracting effect. Biochemistry 53, 5384–5392 (2014)
Ganewatta, M. S. et al. Bio-inspired resin acid-derived materials as anti-bacterial resistance agents with unexpected activities. Chem. Sci. 5, 2011–2016 (2014)
Piggot, T. J., Holdbrook, D. A. & Khalid, S. Electroporation of the E. coli and S. aureus membranes: molecular dynamics simulations of complex bacterial membranes. J. Phys. Chem. B 115, 13381–13388 (2011)
Sala, F. et al. Development and validation of a liquid chromatography–tandem mass spectrometry method for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in plasma of patients in a Phase I study. J. Chromatogr. B 877, 3118–3126 (2009)
Farha, M. A., Verschoor, C. P., Bowdish, D. & Brown, E. D. Collapsing the proton motive force to identify synergistic combinations against Staphylococcus aureus. Chem. Biol. 20, 1168–1178 (2013)
Hurdle, J. G., O’Neill, A. J., Chopra, I. & Lee, R. E. Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat. Rev. Microbiol. 9, 62–75 (2011)
Basma, H. et al. The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma. Int. J. Cancer 138, 1528–1537 (2016)
Cosgrove, S. E. et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin. Infect. Dis. 48, 713–721 (2009)
Álvarez, R., Vaz, B., Gronemeyer, H. & de Lera, A. R. Functions, therapeutic applications, and synthesis of retinoids and carotenoids. Chem. Rev. 114, 1–125 (2014)
Schadendorf, D. et al. Treatment of melanoma cells with the synthetic retinoid CD437 induces apoptosis via activation of AP-1 in vitro, and causes growth inhibition in xenografts in vivo. J. Cell Biol. 135, 1889–1898 (1996)
Langdon, S. P. et al. Growth-inhibitory effects of the synthetic retinoid CD437 against ovarian carcinoma models in vitro and in vivo. Cancer Chemother. Pharmacol. 42, 429–432 (1998)
Ponzanelli, I. et al. Isolation and characterization of an acute promyelocytic leukemia cell line selectively resistant to the novel antileukemic and apoptogenic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid. Blood 95, 2672–2682 (2000)
Acknowledgements
This study was supported by National Institutes of Health grant P01 AI083214 to M.S.G., F.M.A. and E.M., by National Science Foundation grant CMMI-1562904 to H.G., and by National Institute of General Medical Sciences grant 1R35GM119426 and National Science Foundation grant NSF1755698 to W.M.W. D.V.T. is supported by National Eye Institute grant EY028222. We thank the Institute of Chemistry and Cell Biology-Longwood at Harvard Medical School for providing the chemical libraries used in this study. We thank L. Rice for providing the E. faecium strains, K. Bayles and J. Endres for providing plasmid pBK123, J. Saavedra for assistance with next-generation sequencing library preparation, and S. Khalid for providing the atomic structures and force fields of the phosphatidylglycerol, Lys-PG and DPG lipids. The simulations reported were performed on resources provided by the Extreme Science and Engineering Discovery Environment through grant MSS090046 and the Center for Computation and Visualization at Brown University.
Author information
Authors and Affiliations
Contributions
W.K., A.L.C., R.R., B.B.F., F.M.A. and E.M. designed the chemical screen. W.K., B.B.F. and R.R. performed the chemical screen. W.K. designed, performed and analysed MIC assays, dose–response C. elegans infection assays, membrane permeability assays, time-kill assays and transmission electron microscopy experiments. W.K. and D.V.T. designed, performed and analysed the selection of resistant mutants and whole genome sequencing. W.K., N.F. and P.M.V. designed, performed and analysed giant unilamellar vesicle experiments. W.K., W.Z. and H.G. designed, performed and analysed molecular dynamics simulations. A.D.S., C.E.K. and W.M.W. synthesized analogues. W.K. and B.B.F. designed, performed and analysed toxicity tests. W.K., G.L.H., S.S., W.P. and K.L. designed, performed and analysed animal studies. A.L.C., B.B.F., P.M.V., W.M.W., M.S.G., H.G., F.M.A. and E.M. contributed reagents, materials and/or analysis tools. E.M. supervised the project. W.K., W.Z., G.L.H., W.M.W., H.G., F.M.A. and E.M. wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
F.M.A. and E.M. have interests in Genma Biosciences, Inc. and Octagon Therapeutics, Inc., companies that are engaged in developing antimicrobial compounds. The interests of E.M. and F.M.A. were reviewed and are managed by Rhode Island Hospital (E.M.) and Massachusetts General Hospital and Partners HealthCare (F.M.A.) in accordance with their conflict of interest policies. The remaining authors declare no competing interests.
Additional information
Reviewer Information Nature thanks F. DeLeo and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Figure 1 CD437 and CD1530 show fast-killing kinetics and low probability of resistance development, and do not cause detectable cell lysis.
a, Exponential-phase MRSA cells (strain MW2) were treated with 10× MIC CD437, CD1530, adarotene, vancomycin or 0.1% DMSO (negative control). CFU counts of cells were measured by serial dilution and plating on agar plates. The data points on the x axis are below the level of detection (2 × 102 CFU ml−1). Individual data points (n = 3 biologically independent samples) and mean ± s.d. are shown. b, Development of S. aureus MW2 mutants resistant to CD437 (SPCD437), CD1530 (SPCD1530) or daptomycin (SPDap) was attempted by daily serial passage for 15 days. c, Exponential-phase S. aureus MW2 bacteria were treated with 10× MIC CD437, CD1530 or benzalkonium chloride (BAC) for 4 h. The anti-infective detergent BAC was used as a positive control for cell lysis. OD600 was measured in a spectrophotometer every hour. Individual data points (n = 3 biologically independent samples) and mean ± s.d. are shown.
Extended Data Figure 2 All-atom molecular dynamics simulations showing the interactions between selected retinoids or retinoid metabolites and a DOPC:DOPG (7:3) lipid bilayer.
a, Representative configurations of synthetic retinoids or retinoid metabolites at, left to right, the onset of simulation, membrane attachment, membrane penetration and equilibrium state (see Supplementary Methods for atomic rendering). Simulations were repeated five times with similar results. b, c, Free energy profiles of the four retinoids (b) or CD437-metabolites (c) penetrating the membrane as a function of the distance between the COM of the retinoids or the retinoid metabolites and the lipid bilayer. The dot-dashed line marks the membrane surface, averaged from the COM location of phosphate groups in the outer leaflet. Individual data points (n = 3 independent simulations) and mean ± s.d. are shown. The membrane penetration of CD437, CD1530, adarotene, adapalene, the carboxylic-glucuronide metabolite and the phenolic hydroxyl-glucuronide metabolite are associated with transfer energies of −8.92 kBT, −7.14 kBT, −1.45 kBT, 18.76 kBT, −3.73 kBT, −2.02 kBT and energy barriers of 1.42 kBT, 1.12 kBT, 2.03 kBT, 26.13 kBT, 5.01 kBT, 7.40 kBT, respectively.
Extended Data Figure 3 CD437 and CD1530 kill MRSA persisters by inducing membrane permeabilization.
a, S. aureus MW2 persisters were treated with the indicated concentrations of the retinoids. Membrane permeability was measured spectrophotometrically by monitoring the uptake of SYTOX Green (λex = 485 nm, λem = 525 nm) over time. Individual data points (n = 2 biologically independent samples) and means are shown; error bars are not shown for clarity. b–d, Stationary-phase S. aureus MW2 (b) or stationary-phase cells of 11 clinical S. aureus isolates were treated with 100× MIC conventional antibiotics (c) or 10× MIC retinoids (d) for 4 h. Viability was measured by serial dilution and plating on agar plates. The data points on the x axis are below the level of detection (2 × 102 CFU ml−1). b–d, Individual data points (n = 3 biologically independent samples) and mean ± s.d. are shown.
Extended Data Figure 4 CD437 or CD1530 alone or in combination with gentamicin eliminate persisters formed in MRSA biofilms.
MRSA MW2 biofilms formed on 13 mm cellulose ester membranes were treated with the indicated concentrations of retinoids alone or in combination with gentamicin. The number of viable cells in biofilms was measured by CFU counting. The data points on the x axis are below the level of detection (2 × 102 CFU ml−1). Individual data points (n = 3 biologically independent samples) and mean ± s.d. are shown.
Extended Data Figure 5 Ionophores do not induce SYTOX Green membrane permeabilization or kill MRSA MW2 persisters.
a, Synergism between nigericin and gentamicin was evaluated against S. aureus MW2 by the fractional inhibitory concentration index (FICI) microdilution checkerboard method. Optical densities at 600 nm were measured after 18 h incubation at 37 °C. Experiments were independently repeated twice with similar results. Synergy, FICI ≤ 0.5; no interaction, 0.5 < FICI ≤ 4; antagonism, FICI > 4. b, Exponential-phase MW2 cells were treated with the indicated concentrations of valinomycin, nigericin or monensin. Membrane permeability was measured spectrophotometrically by monitoring the uptake of SYTOX Green (λex = 485 nm, λem = 525 nm) over time. Individual data points (n = 2 biologically independent samples) are shown; error bars are not shown for clarity. c–e, Stationary-phase S. aureus MW2 was treated with the indicated concentrations of ionophores, alone or combined with 10× MIC gentamicin (Gm), or 0.1% DMSO (control) for 4 h. Viability was measured by serial dilution and plating on agar plates. Individual data points (n = 3 biologically independent samples) and mean ± s.d. are shown.
Extended Data Figure 6 Evaluation of cytotoxic potentials of retinoids in various cell lines.
a, Measurement of haemolytic activity. 2% human erythrocytes were treated with twofold serially diluted concentrations of the retinoids for 1 h at 37 °C. A sample treated with 1% Triton X-100 was used as the control for 100% haemolysis. b, Normal rat, human primary hepatocytes, human hepatoma (HepG2) cells, normal human primary renal proximal tubule epithelial cells (RPTEC) or adult normal human epidermal keratinocytes (NHEK) were treated with a range of concentrations of the synthetic retinoids in chemically defined, serum-free medium for 24 h. The FDA-approved antineoplastic retinoid bexarotene was used as a control. Cell viability was calculated on the basis of absorbance readings at 450 nm at 4 h after adding WST-1. a, b, Individual data points (n = 3 biologically independent samples) and mean ± s.d. are shown. c, Three synthetic retinoids and the positive control quinidine were tested for inhibition of the hERG potassium channel. Individual data points (n = 4 biologically independent samples) and mean ± s.d. are shown. Data are fitted to a standard inhibition curve.
Extended Data Figure 7 Structure-activity relationships.
a, The chemical structures of newly synthesized CD437 analogues. b, MICs and membrane permeability were measured for S. aureus strain MW2. Membrane permeability was evaluated spectrophotometrically by monitoring the uptake of SYTOX Green (λex = 485 nm, λem = 525 nm) over time. Individual data points (n = 2 biologically independent samples) and means are shown; error bars are not shown for clarity.
Extended Data Figure 8 Determination of the biological properties of analogues 2 and 9.
a, b, Human erythrocytes were treated for 1 h (a) and rat primary hepatocytes were treated for 24 h (b) with analogues 2 and 9. c, MRSA MW2 persisters were treated with analogue 9. The data points on the x axis are below the level of detection (2 × 102 CFU ml−1). a–c, Individual data points (n = 3 biologically independent samples) and mean ± s.d. are shown. d, Representative configurations of molecular dynamics simulations of analogue 2 interacting with lipid bilayers (108 phosphatidylglycerol lipids, 72 Lys-PG lipids and 10 DPG lipids; see Supplementary Methods for atomic rendering). Simulations were repeated five times with similar results. e, Free energy profiles of analogue 2, CD437 and adarotene penetrating the membrane as a function of the distance between the COM of the retinoids and the lipid bilayer. The dot-dashed line marks the membrane surface, averaged from the COM location of phosphate groups in outer leaflet. Individual data points (n = 3 independent simulations) and mean ± s.d. are shown. f, The plasma concentrations of analogue 2 after a single injection of analogue 2 (20 mg kg−1, i.p., 3 mice per time point) were measured using LC–MS/MS. Pharmacokinetic analysis was conducted using Phoenix WinNonlin software version 6.3. Individual data points (n = 3 biologically independent animals) and mean ± s.d. are shown. The determined pharmacokinetic parameters are Tmax (the time taken to reach the maximum concentration) 0.5 h, Cmax (maximum concentration observed) 16.14 μg ml−1, AUClast (area under the curve to last time point) 16.38 h·μg ml−1, AUCinf (area under the curve to infinite) 16.54 h·μg ml−1, t1/2 (half-life) 4.49 h, clearance 20.16 ml min−1 kg−1. g, Six mice per group (n = 6 biologically independent animals) were treated with control (5% Kolliphor + 5% ethanol, i.p.), vancomycin (25 mg kg−1, i.p.) or analogue 2 (10–80 mg kg−1, i.p.) every 12 h for 3 days. At 12 h after the last treatment, alanine aminotransferase (ALT) and blood urea nitrogen (BUN) were analysed. The concentrations of ALT (in international units per litre, IU l−1) and BUN (mg dl−1) in each mouse serum sample analysed are plotted as individual points and the mean ± s.d. is shown. Control and antibiotic treatments were analysed by one-way ANOVA and post hoc Tukey test, which demonstrated a lack of significant differences (P > 0.7 for all ALT and BUN samples).
Extended Data Figure 9 The charges and the number of branch groups affects membrane activity of CD437-like retinoids.
a, Comparison of partial atomic charges between CD437 and analogue 3. b, Representative configurations of molecular dynamics simulations of analogues 3, 11, and 14 interacting with lipid bilayers (DOPC:DOPG, 7:3). The amide group in analogue 3 is repelled away from the membrane despite the attachment of the hydroxyl group. Atomic rendering is described in Supplementary Methods. Simulations were repeated five times with similar results. c, d, Free energy profiles of analogue 3 penetrating DOPC:DOPG (7:3) lipid bilayers (c) and CD437 penetrating differently charged lipid bilayers (d). e, Analogues 11 and 14 penetrating DOPC:DOPG (7:3) lipid bilayers as a function of the distance between the COM of the retinoids and the lipid bilayer. The dot-dashed line marks the membrane surface, averaged from the COM location of phosphate groups in the outer leaflet. c–e, Individual data points (n = 3 independent simulations) and mean ± s.d. are shown.
Extended Data Figure 10 In vivo efficacy of CD437 alone or in combination with gentamicin in a deep-seated mouse thigh infection model.
We chose a dose of 20 mg kg−1 CD437 to test its in vivo efficacy in the MRSA mouse deep-seated thigh infection model, because a dose of 20 mg kg−1 has shown in vivo efficacy in mouse xenograft cancer models27,28,29. Ten MRSA MW2-infected mice per group (n = 10 biologically independent animals, see Supplementary Methods) were treated with control (5% Kolliphor + 5% ethanol, i.p.), vancomycin (25 mg kg−1, i.p.), gentamicin (30 mg kg−1, s.c.), CD437 (20 mg kg−1, i.p.), or a combination of CD437 (20 mg kg−1, i.p.) and gentamicin (30 mg kg−1, s.c.) every 12 h for 3 days beginning 24 h after infection. At 12 h after the last treatment, mice were euthanized and their thighs were excised and homogenized, and blood was collected and analysed for ALT and BUN. a, CFUs from each mouse thigh are plotted as individual points and the mean ± s.d. for each experimental group is shown. b, c, Concentration of ALT for each mouse serum sample (b) and absorbance of BUN at 340 nm (c) are plotted as individual points. The mean ± s.d. for each experimental group is shown. Statistical differences between control and antibiotic treatment groups were analysed by one-way ANOVA and post hoc Tukey test (***P < 0.0001).
Supplementary information
Supplementary Information
This file contains Supplementary Tables 1-9, full legends for Supplementary Videos 1-17, a Supplementary Discussion, Supplementary Methods, Supplementary Figure 1, Supplementary References and NMR Spectra (Supplementary Figures 2-61). (PDF 3505 kb)
Supplementary Videos 1-5
CD437, CD1530, and adarotene disrupt GUVs. GUVs consisting of DOPC/DOPG (7:3) labeled with 18:1 Liss Rhod PE (0.05%) were treated with 10 µg/ml (10X MIC) CD437 (Supplementary Video 1), 10 µg/ml (10X MIC) CD1530 (Supplementary Video 2), 20 µg/ml (10X MIC) adarotene (Supplementary Video 3), 20 µg/ml adapalene (Supplementary Video 4), or 0.1% DMSO (Supplementary Video 5). After adding compounds at t=0 sec, changes in each GUV were recorded using a fluorescent microscope (63x objective, Ex=460 nm, Em=483 nm). Experiments were repeated 3 times with similar results. (ZIP 7327 kb)
Supplementary Videos 6-9
Molecular dynamics of CD437 (Supplementary Video 6), CD1530 (Supplementary Video 7), adarotene (Supplementary Video 8) and adapalene (Supplementary Video 9) interacting with mixed 108PG/72lys PG/10DPG lipid bilayers. In the videos of MD simulations, the retinoids and sodium ions are depicted as large spheres, and phospholipids are represented as chains. The atoms in retinoids, phospholipids and sodium ions are colored as follows: hydrogen, white; oxygen, red; nitrogen, dark blue; carbon, cyan; phosphorus, orange; sodium, lavender. Water molecules are set to be transparent for clarity. The outer blue lines indicate the period boundaries of the simulation boxes. Simulations were repeated 5 times with similar results. (ZIP 51348 kb)
Supplementary Videos 10-13
Molecular dynamics of CD437 (Supplementary Video 10), CD1530 (Supplementary Video 11), adarotene (Supplementary Video 12) and adapalene (Supplementary Video 13) interacting with mixed lipid bilayers at a DOPC:DOPG ratio of 7:3. In the videos of MD simulations, the retinoids and sodium ions are depicted as large spheres, and phospholipids are represented as chains. The atoms in retinoids, phospholipids and sodium ions are colored as follows: hydrogen, white; oxygen, red; nitrogen, dark blue; carbon, cyan; phosphorus, orange; sodium, lavender. Water molecules are set to be transparent for clarity. The outer blue lines indicate the period boundaries of the simulation boxes. Simulations were repeated 5 times with similar results. (ZIP 30331 kb)
Supplementary Videos 14-15
Molecular dynamics of CD437 carboxylic glucuronide (Supplementary Video 14) and phenolic hydroxyl glucuronide (Supplementary Video 15) interacting with mixed lipid bilayers at a DOPC:DOPG ratio of 7:3. In the videos of MD simulations, the CD437-glucuronides and sodium ions are depicted as large spheres, and phospholipids are represented as chains. The atoms in CD437-glucuronides, phospholipids and sodium ions are colored as follows: hydrogen, white; oxygen, red; nitrogen, dark blue; carbon, cyan; phosphorus, orange; sodium, lavender. Water molecules are set to be transparent for clarity. The outer blue lines indicate the period boundaries of the simulation boxes. Simulations were repeated 5 times with similar results. (ZIP 17484 kb)
Supplementary Videos 16-17
Supplementary Video 16 shows the molecular dynamics of Analog 2 interacting with mixed 108PG/72lys PG/10DPG lipid bilayers. In the videos of MD simulations, Analog 2 and sodium ions are depicted as large spheres, and phospholipids are represented as chains. The atoms in Analog 2, phospholipids and sodium ions are colored as follows: hydrogen, white; oxygen, red; nitrogen, dark blue; carbon, cyan; phosphorus, orange; sodium, lavender. Water molecules are set to be transparent for clarity. The outer blue lines indicate the period boundaries of the simulation boxes. Simulations were repeated 5 times with similar results. Supplementary Video 17 shows the molecular dynamics of Analog 3 interacting with mixed lipid bilayers at a DOPC:DOPG ratio of 7:3. In the videos of MD simulations, Analog 3 and sodium ions are depicted as large spheres, and phospholipids are represented as chains. The atoms in Analog 3, phospholipids and sodium ions are colored as follows: hydrogen, white; oxygen, red; nitrogen, dark blue; carbon, cyan; phosphorus, orange; sodium, lavender. Water molecules are set to be transparent for clarity. The outer blue lines indicate the period boundaries of the simulation boxes. Simulations were repeated 5 times with similar results. (ZIP 22991 kb)
Source data
Rights and permissions
About this article
Cite this article
Kim, W., Zhu, W., Hendricks, G. et al. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556, 103–107 (2018). https://doi.org/10.1038/nature26157
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature26157
This article is cited by
-
Repurposing CD5789 as an Antimicrobial Agent Against MRSA and Its High Resistant Phonotypes
Current Microbiology (2023)
-
A self-activated NO-releasing hydrogel depot for photothermal enhanced sterilization
Nano Research (2023)
-
Antibacterial metal nanoclusters
Journal of Nanobiotechnology (2022)
-
A potent antibiotic-loaded bone-cement implant against staphylococcal bone infections
Nature Biomedical Engineering (2022)
-
Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
Nature Communications (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
