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Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice


The clinical translation of cationic α-helical antimicrobial peptides (AMPs) has been hindered by structural instability, proteolytic degradation and in vivo toxicity from nonspecific membrane lysis. Although analyses of hydrophobic content and charge distribution have informed the design of synthetic AMPs with increased potency and reduced in vitro hemolysis, nonspecific membrane toxicity in vivo continues to impede AMP drug development. Here, we analyzed a 58-member library of stapled AMPs (StAMPs) based on magainin II and applied the insights from structure–function–toxicity measurements to devise an algorithm for the design of stable, protease-resistant, potent and nontoxic StAMP prototypes. We show that a lead double-stapled StAMP named Mag(i+4)1,15(A9K,B21A,N22K,S23K) can kill multidrug-resistant Gram-negative pathogens, such as colistin-resistant Acinetobacter baumannii in a mouse peritonitis–sepsis model, without observed hemolysis or renal injury in murine toxicity studies. Inputting the amino acid sequences alone, we further generated membrane-selective StAMPs of pleurocidin, CAP18 and esculentin, highlighting the generalizability of our design platform.

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Fig. 1: Antimicrobial and hemolytic activities of an i, i+4-stapled Mag2 library.
Fig. 2: Hydrophobic network mapping predicts mammalian cell lysis.
Fig. 3: Transmembrane insertion mechanism of bacterial-selective StAMPs.
Fig. 4: Biophysical, biological and safety profile of a double-stapled StAMP.
Fig. 5: Optimized properties of a lead StAMP for preclinical development.
Fig. 6: Computational design of diverse membrane-selective StAMPs.

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We thank D. Hung and R. Bhattacharyya for providing clinical strains of MDR bacteria, K. Kean and P. Barendse for coding assistance, K. Hanford and M. Godes for technical support, A. Watts for helpful discussions, M. Cameron for plasma stability analyses, S. Breegi, C. Sypher and the Dana-Farber Cancer Institute Animal Resource Facility for technical assistance with in vivo studies, D. Neuberg for biostatistical support and R. Bronson for histopathology services and expert slide review. We are also grateful to the Centers for Disease Control and Prevention Antimicrobial Resistance Isolate Bank that provided access to panels of MDR bacteria. This research was supported by a National Institutes of Health grant no. R35CA197583 and a Leukemia and Lymphoma Society Scholar Award to L.D.W. Additional support to L.D.W. was generously provided by the LaTorre Family, the Wolpoff Family Foundation and the Todd J. Schwartz Memorial Fund. The Charles River toxicity study was supported in part by an option agreement between the Dana-Farber Cancer Institute and Aileron Therapeutics. This research was also supported by a National Institutes of Health grant no. R01GM101135 to J.R.E. and a research collaboration between J.R.E. and the Waters Corporation. R.M.’s doctoral research was supported in part by a Doctoral Foreign Study Award (no. DFS-134963) from the Canadian Institutes of Health Research and an IDEA-squared award from the Harvard-MIT Division of Health Sciences and Technology.

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Authors and Affiliations



R.M. and L.D.W. conceived of and designed the study. R.M. synthesized and characterized StAMPs, performed the biochemical and cellular experiments and collaborated with H.D.H. on developing the hydrophobicity network map analysis and performing the in vivo studies. D.Y. conducted the QCM experiments. J.A.M. performed the HX–MS analyses under the supervision of T.E.W. and J.R.E. The paper was written by L.D.W., R.M. and H.D.H., and reviewed by all co-authors.

Corresponding author

Correspondence to Loren D. Walensky.

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L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics.

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Integrated supplementary information

Supplementary Figure 1 Antimicrobial and hemolytic activities of an i, i+7-stapled Mag2 library.

The antimicrobial activity (MIC in μg/mL) and percent RBC hemolysis at 25 μg/mL were determined for a library of i, i+7 stapled peptides based on the Mag2 sequence. The MIC is the geometric mean of four independent experiments. Percent hemolysis data are the mean of three independent experiments (shown as dots). X, S5 stapling amino acid; 8, R8 stapling amino acid; B, norleucine (substituted for methionine to maximize the efficiency of ruthenium-catalyzed olefin metathesis).

Supplementary Figure 2 Relationships between StAMP biophysical parameters and hemolysis.

a-e, No direct correlations were observed between percent RBC hemolysis and the total hydrophobicity (a), percent α-helicity (b), HPLC retention time (c), pI (d), or 3D hydrophobic moment magnitude (e) of StAMPs (n=19), as calculated by Pearson correlation.

Supplementary Figure 3

A computational algorithm yields HNMs and lyticity indices for StAMPs.

Supplementary Figure 4

HNMs and lyticity indices of a staple-scanning Mag(i+4) library

Supplementary Figure 5

HNMs and lyticity indices of a lysine-scanning Mag(i+4)15 library

Supplementary Figure 6 Membrane selectivity and insertion mechanism of Mag(i+4)15(A9K).

a, Incubation of Mag(i+4)1,15(A9K) with anionic liposomes that mimic E. coli membranes (POPC:POPG) reduces deuterium exchange, whereas exposure to zwitterionic liposomes that mimic the mammalian membrane condition (POPC:Cholesterol) has no such effect and is identical to the peptide’s deuterium exchange profile in aqueous solution alone. HX-MS experiments were performed independently three times with similar results. b-e, QCM sensorgrams demonstrate uniformity of changes in resonant frequency across harmonics for SLBs mimicking bacterial membranes (POPC:POPG) upon exposure to 6 (b) and 24 (c) μg/mL of Mag(i+4)1,15(A9K), consistent with transmembrane insertion. In contrast, little to no interaction is reflected in the QCM profiles of POPC mammalian-type membranes at low or high peptide dosing (d-e). For each condition, an exemplary sensorgram is shown for experiments performed independently two times with similar results. f, Accordingly, there were no changes in resonant frequency across the third (blue), seventh (red), and eleventh (black) harmonics in response to Mag(i+4)1,15(A9K) treatment (8 μg/mL) of SLBs composed of POPC and increasing concentrations of cholesterol. Data are mean of two independent experiments (shown as dots).

Supplementary Figure 7 Body weights of mice treated intravenously with Mag(i+4)1,15(A9K).

Mice were treated with Mag(i+4)15(A9K) at an intravenous dose of 5 mg/kg twice daily for 8 days. Body weights were measured before (day 1) and after 8 days of treatment (day 9). Data are mean ± s.d. for n=4 mice per sex.

Supplementary Figure 8 Histology of murine tissues after IV treatment with Mag(i+4)1,15(A9K).

Peripheral blood smears (a-d) and H&E stained sections of liver (e-h) and kidney (h-k) from n=8 mice (4 male, 4 female) treated with Mag(i+4)15(A9K) (5 mg/kg IV BID x 8 d). Each vertical pair (a-b, c-d, e-f, g-h, h-i, j-k) represents a low and higher power view (enlargement of boxed image) of the indicated tissue. For each tissue, specimens from two different mice are shown. RBC morphology and liver histology are normal. Whereas some of the treated mice showed predominantly normal kidney histology (h-k), others manifested regions of mild-to-moderate tubular degeneration, as shown in Fig. 4j and Supplementary Fig. 12b.

Supplementary Figure 9 RBC response to Mag(i+4)15(A9K,B21A,N22K,S23K) treatment.

Mag(i+4)15(A9K,B21A,N22K,S23K) shows little to no RBC hemolytic activity across a broad dose-effective range, and even when dosed as high as 800 μg/mL for 90 minutes or 18 hours. The data from two independently performed experiments are shown as dots, with several pairs of replicate data points overlapping. The Gram-negative bactericidal dosing range is highlighted in yellow in the inset.

Supplementary Figure 10 Comparative activity of linear and stapled Mag2 peptides in a peritonitis-sepsis mouse model.

a, Kaplan Meier survival curves of neutropenic mice (n=8 per arm) infected with A. baumannii (ATCC 19606) intraperitoneally and treated with either vehicle (saline) or two 5 mg/kg IP doses of Mag(i+4)15(A9K,B21A,N22K,S23K). p=0.0006 for StAMP vs. vehicle by log rank test (two-sided). b, Kaplan Meier survival curves of neutropenic mice (n=8 per arm) infected with A. baumanii (AR-0303) intraperitoneally and treated with either vehicle (saline) or two 5 mg/kg IP doses of Mag2 or Mag(i+4)15(A9K,B21A,N22K,S23K). p=0.0001 for StAMP vs. Vehicle; p=0.02 for StAMP vs. Mag2; and p=0.1432 (n.s.) for Mag2 vs. Vehicle, as calculated by log rank test (two-sided).

Supplementary Figure 11 Body weights of StAMP-treated mice.

Mice were treated with vehicle or Mag(i+4)15(A9K,B21A,N22K,S23K) at an intravenous dose of 5 mg/kg twice daily for 5 days. Body weights were measured before (day 1) and after 5 days of treatment (day 6). Data are mean ± s.d. for n=8 female mice per arm.

Supplementary Figure 12 Histology of murine kidney after intravenous treatment with StAMPs.

a-b, Mice (n=8 per arm) were treated with vehicle, Mag(i+4)15(A9K,B21A,N22K,S23K), or Mag(i+4)15(A9K) at an intravenous dose of 5 mg/kg twice daily for 5 days. H&E stained sections of kidney tissue from mice treated with Mag(i+4)15(A9K,B21A,N22K,S23K) showed normal histology (a), whereas select mice treated with Mag(i+4)15(A9K) manifested mild-to-moderate renal tubule degeneration (b) (affected regions outlined in dashed black lines). For each image pair, the boxed tissue on the left is enlarged in the image to the right.

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Mourtada, R., Herce, H.D., Yin, D.J. et al. Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice. Nat Biotechnol 37, 1186–1197 (2019).

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