journal article·2022-02-22

Synthetic Antibiotic Derived from Sequences Encrypted in a Protein from Human Plasma

Angela Cesaro, Marcelo D. T. Torres, Rosa Gaglione, Eliana Dell’Olmo, Rocco Di Girolamo, Andrea Bosso, Elio Pizzo, Henk P. Haagsman, Edwin J. A. Veldhuizen, Cesar de la Fuente-Nunez, Angela Arciello

ACS Nano· Volume 16· Issue 2
Publisher page

Abstract

Encrypted peptides have been recently found in the human proteome and represent a potential class of antibiotics. Here we report three peptides derived from the human apolipoprotein B (residues 887–922) that exhibited potent antimicrobial activity against drug-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococci both in vitro and in an animal model. The peptides had excellent cytotoxicity profiles, targeted bacteria by depolarizing and permeabilizing their cytoplasmic membrane, inhibited biofilms, and displayed anti-inflammatory properties. Importantly, the peptides, when used in combination, potentiated the activity of conventional antibiotics against bacteria and did not select for bacterial resistance. To ensure translatability of these molecules, a protease resistant retro-inverso variant of the lead encrypted peptide was synthesized and demonstrated anti-infective activity in a preclinical mouse model. Our results provide a link between human plasma and innate immunity and point to the blood as a source of much-needed antimicrobials.
Source: openalex_inverted_index · Quality: baseline

Research context

OpenAlex topics: Antimicrobial Peptides and Activities · Biochemical and Structural Characterization · Bacteriophages and microbial interactions

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Chemical Sciences, University of Naples Federico II, Naples I-80126, Italy

Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Section Molecular Host Defence, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CL, The Netherlands

Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States

Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States

Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States

Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome 00136, Italy

Department of Biology, University of Naples Federico II, Naples I-80126, Italy

Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Section Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CL, The Netherlands

Funding

Ministero dell?Istruzione, dell?Universit? e della Ricerca · Defense Threat Reduction Agency · National Institute of General Medical Sciences

References (78)

Show source-provided references
1. 10.1155/2016/247506710.1155/2016/2475067 ↗
2. CDC. Antibiotic/Antimicrobial Resistance (AR/AMR) Threats Report. https://www.cdc.gov/drugresistance/biggest-threats.html (accessed 2021-12-27).
3. 10.3389/fmicb.2019.0053910.3389/fmicb.2019.00539 ↗
4. 10.3389/fphar.2018.0028110.3389/fphar.2018.00281 ↗
5. 10.1111/febs.1372510.1111/febs.13725 ↗
6. 10.1016/j.bcp.2017.01.00910.1016/j.bcp.2017.01.009 ↗
7. 10.1038/s41551-021-00801-110.1038/s41551-021-00801-1 ↗
8. 10.2174/156802662066620042709145410.2174/1568026620666200427091454 ↗
9. 10.1021/acssynbio.8b0008410.1021/acssynbio.8b00084 ↗
10. 10.1016/j.drudis.2006.02.00310.1016/j.drudis.2006.02.003 ↗
11. 10.1002/bip.2068710.1002/bip.20687 ↗
12. 10.1016/j.bcp.2017.01.00910.1016/j.bcp.2017.01.009 ↗
13. 10.1111/febs.1372510.1111/febs.13725 ↗
14. 10.1038/s41598-019-43063-310.1038/s41598-019-43063-3 ↗
15. 10.12688/f1000research.9845.110.12688/f1000research.9845.1 ↗
16. 10.1128/CMR.00040-0910.1128/CMR.00040-09 ↗
17. 10.1161/01.ATV.19.12.296610.1161/01.ATV.19.12.2966 ↗
18. 10.1111/j.1348-0421.2010.00203.x10.1111/j.1348-0421.2010.00203.x ↗
19. 10.1016/j.jtbi.2017.02.01210.1016/j.jtbi.2017.02.012 ↗
20. 10.1016/j.nbt.2019.02.00410.1016/j.nbt.2019.02.004 ↗
21. 10.1038/nprot.2007.52110.1038/nprot.2007.521 ↗
22. 10.1007/s00253-015-6926-110.1007/s00253-015-6926-1 ↗
23. 10.1016/j.chembiol.2013.09.00210.1016/j.chembiol.2013.09.002 ↗
24. 10.3389/fcell.2016.0002910.3389/fcell.2016.00029 ↗
25. 10.1371/journal.pone.014791910.1371/journal.pone.0147919 ↗
26. 10.1016/j.molimm.2009.05.01910.1016/j.molimm.2009.05.019 ↗
27. 10.3390/antibiotics902009210.3390/antibiotics9020092 ↗
28. 10.1371/journal.pone.008002510.1371/journal.pone.0080025 ↗
29. 10.1038/srep1726010.1038/srep17260 ↗
30. 10.1128/AAC.44.12.3317-3321.200010.1128/AAC.44.12.3317-3321.2000 ↗
31. 10.3390/molecules2305122010.3390/molecules23051220 ↗
32. 10.1128/AAC.00682-1510.1128/AAC.00682-15 ↗
33. 10.1128/AAC.03163-1410.1128/AAC.03163-14 ↗
34. 10.1021/acsinfecdis.0c0001610.1021/acsinfecdis.0c00016 ↗
35. 10.1016/j.chembiol.2015.01.00210.1016/j.chembiol.2015.01.002 ↗
36. 10.1073/pnas.201237911710.1073/pnas.2012379117 ↗
37. 10.18773/austprescr.2019.00110.18773/austprescr.2019.001 ↗
38. 10.1021/acsnano.0c0950910.1021/acsnano.0c09509 ↗
39. 10.1016/j.jmb.2018.12.01510.1016/j.jmb.2018.12.015 ↗
40. 10.1371/journal.pone.022901910.1371/journal.pone.0229019 ↗
41. 10.1371/journal.pone.012023810.1371/journal.pone.0120238 ↗
42. 10.3389/fmicb.2020.0010310.3389/fmicb.2020.00103 ↗
43. 10.1186/s12866-014-0253-z10.1186/s12866-014-0253-z ↗
44. 10.1128/AAC.00064-1210.1128/AAC.00064-12 ↗
45. 10.1002/bies.20140012810.1002/bies.201400128 ↗
46. 10.1186/1752-153X-5-4810.1186/1752-153X-5-48 ↗
47. Veas F. · 201110.5772/756 ↗
48. 10.1371/journal.pone.006046210.1371/journal.pone.0060462 ↗
49. 10.3390/molecules2512285010.3390/molecules25122850 ↗
50. 10.1016/j.ejps.2019.06.00610.1016/j.ejps.2019.06.006 ↗
51. 10.1038/srep2082310.1038/srep20823 ↗
52. 10.4103/2277-9175.11419210.4103/2277-9175.114192 ↗
53. 10.1371/journal.pone.008280010.1371/journal.pone.0082800 ↗
54. 10.1007/s10096-016-2647-310.1007/s10096-016-2647-3 ↗
55. 10.3389/fmicb.2019.0310610.3389/fmicb.2019.03106 ↗
56. 10.5114/aoms.2018.7402110.5114/aoms.2018.74021 ↗
57. 10.1371/journal.ppat.100316610.1371/journal.ppat.1003166 ↗
58. 10.1517/17425255.2011.57412610.1517/17425255.2011.574126 ↗
59. 10.1016/j.bbamem.2017.09.00810.1016/j.bbamem.2017.09.008 ↗
60. 10.1371/journal.pone.017894310.1371/journal.pone.0178943 ↗
61. 10.1073/pnas.171183711510.1073/pnas.1711837115 ↗
62. Cardoso M. H. · 2018 · 13110.1016/B978-0-08-100736-5.00005-3 ↗
63. 10.1038/s41598-018-27231-510.1038/s41598-018-27231-5 ↗
64. 10.1038/s42003-018-0224-210.1038/s42003-018-0224-2 ↗
65. 10.1016/j.ejmech.2016.11.04010.1016/j.ejmech.2016.11.040 ↗
66. 10.1002/psc.302910.1002/psc.3029 ↗
67. 10.1002/slct.20160159010.1002/slct.201601590 ↗
68. 10.1080/21553769.2019.162259610.1080/21553769.2019.1622596 ↗
69. 10.1093/jac/dkq30210.1093/jac/dkq302 ↗
70. 10.1186/s13104-016-1902-010.1186/s13104-016-1902-0 ↗
71. 10.1586/14787210.2015.102329110.1586/14787210.2015.1023291 ↗
72. 10.3390/ph1407063110.3390/ph14070631 ↗
73. 10.1023/A:101895330991310.1023/A:1018953309913 ↗
74. 10.1002/slct.20160159010.1002/slct.201601590 ↗
75. 10.3390/ijms2106204910.3390/ijms21062049 ↗
76. 10.1016/j.fm.2021.10380410.1016/j.fm.2021.103804 ↗
77. 10.3390/ijms2106204910.3390/ijms21062049 ↗
78. 10.1016/j.bbagen.2017.06.00910.1016/j.bbagen.2017.06.009 ↗