Antimicrobial Peptides and Cell-Penetrating Peptides: Non-Antibiotic Membrane-Targeting Strategies Against Bacterial Infections

Figures & data

Figure 1 Different structures of AMPs. (A) Clavanin A, fowlicidin-1 and plantaricin A have typical α-helical conformations. (B) Gomesin, hepcidin-20 and thanatin have β-sheet conformations. (C) Termicin, phormicin and plectasin have both alpha-helix and beta-sheet conformations. (D) Drosocin, indolicidin and tritrpticin are AMPs with linear extension structures. All the structures were taken from the DBAASP v3: database.¹¹²

Figure 2 Three models of action for extracellular AMP activity include the carpet model, barrel stave model and toroidal pore model.¹¹⁴

Notes: Reproduced from Huan Y, Kong Q, Mou H and Yi H (2020) Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields. Front. Microbiol. 11:582779. Creative Commons Attribution License (CC BY).¹¹⁴

Table 1 Selection of AMPs in Clinical Phase of Development

AMPs	Sequence or Source	Application	Status	Compounds	ClinicalTrial.gov ID	Locations
Polymyxins	XTXXXlLXXT	Gram-Negative Bacterial Infections, Sepsis, Septic Shock	Phase 4 (completed 2008)	Polymyxin B	NCT00629382	Italy
		Gram-Negative Bacterial Infections, Colistin Adverse Reaction	Phase 4 (completed 2019)	Colistimethate Sodium	NCT03397914	Egypt
		Hematological Infection	Phase 4 (completed 2017)	Colistimethate Sodium	NCT02966457	Belarus
		Vaginitis	Phase 4 (completed 2008)	Polygynax	NCT02444481	France
		Vaginitis	Phase 3 (completed 2016)	POLYGYNAX^®	NCT02515656	Slovakia
		Gram-Negative Bacterial Infections	Phase 3 (completed 2007)	Polymyxin B	NCT00490477	Italy
		Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, Bacteremia	Phase 3 (completed 2021)	Colistin	NCT03894046	United States
		Ventilator Associated Pneumonia	Phase 3 (completed 2018)	Colistin	NCT03622450	Egypt
		Eczematous dermatitis	Phase 3 (completed 2012)	Polymyxin B sulphate	NCT01429701	France
		Peritonitis, Septic Shock	Phase 3 (completed 2013)	Polymyxin B	NCT01222663	France
Daptomycin	Lipopeptide	Methicillin Susceptible Staphylococcus Aureus Septicemia, Bacteremia	Phase 4 (completed 2019)	Daptomycin	NCT02972983	Canada
		Staphylococcal Skin Infections	Phase 4 (completed 2012)	Daptomycin	NCT01419184	United States
		Wound Infection	Phase 4 (completed 2012)	Daptomycin	NCT01080963	Germany
		Cellulitis, Skin Infections	Phase 4 (completed 2013)	Daptomycin	NCT01549613	United States
		Cellulitis	Phase 4 (completed 2006)	Daptomycin	NCT01626560, NCT00295178	Brazil, United States
		Skin Diseases, Infectious	Phase 4 (completed 2013)	Daptomycin	NCT00711802	United States
Surotomycin (CB-183,315)	Analogue of Daptomycin	Clostridium difficile infections; Diarrhea	Phase 2 (completed 2011)	CB-183,315	NCT01085591	United States
		Clostridium Difficile Infection	Phase 3 (completed 2015)	Surotomycin	NCT01597505 NCT01598311	United States
Bacitracin	ICLeIKxIfHdN	Surgical Wound Infection, Surgical Site Infection	Phase 4 (completed 2019)	Bacitracin	NCT03199911	United States
		Skin Infection	Phase 4 (completed 2020)	Bacitracin	NCT03929224	United States
Pexiganan	GIGKFLKKAKKFGKAFVKILKK	Diabetic Foot Infection	Phase 3 (completed 2016)	Pexiganan	NCT01594762	United States
Omiganan	ILRWPWWPWRRK	Rosacea	Phase 3 (completed 2018)	Omiganan, CLS001	NCT02576847, NCT02547441	United States
		Infection	Phase 3 (completed 2008)	Omiganan 1% gel	NCT00608959	United States
		Atopic Dermatitis	Phase 2 (completed 2017)	Omiganan	NCT03091426	Netherlands
		Condylomata Acuminata (External)	Phase 2 (completed 2017)	Omiganan (CLS001)	NCT02849262	Netherlands
		Acne Vulgaris	Phase 2 (completed 2016)	Omiganan (CLS001)	NCT02571998	United States
		Papulopustular Rosacea	Phase 2 (completed 2013)	Omiganan	NCT01784133	United States
Voxvoganan (LTX-109)	Peptidomimetic, arginine-tertbutyl tryptophan-arginine-phenylethan	Hidradenitis Suppurativa	Phase 2 (completed 2021)	LTX-109 gel, 3% w/w	NCT04756336	Norway
		Non-bullous Impetigo	Phase 2 (completed 2014)	LTX-109 1% and 2%	NCT01803035	Dominican Republic
		Nasal Decolonization of Staphylococcus Aureus	Phase 2 (completed 2021)	LTX-109 gel, 3% w/w	NCT04767321	Sweden
		Gram-positive Skin Infections, Atopic Dermatitis	Phase 2 (completed 2011)	LTX-109	NCT01223222	Hungary
		Nasal Carriers Methicillin-resistant Staphylococcus Aureus	Phase 2 (completed 2011)	LTX-109	NCT01158235	Sweden
DPK-060	GKHKNKGKKNGKHNGWKWWW	Acute Otitis Externa	Phase 2 (completed 2012)	DPK-060	NCT01447017	Sweden
		Atopic Dermatitis	Phase 2 (completed 2009)	DPK-060 1% ointment	NCT01522391	Sweden
hLF1-11	GRRRRSVQWCA	Bacterial Infections	Phase 2 (completed 2006)	Human lactoferrin peptide 1–11	NCT00509938	Netherlands
LL-37	LLGDLLRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES	Melanoma	Phase 2 (completed 2020)	LL37	NCT02225366	United States
C16G2	TFFRLFNRSFTQALGKGGGKNLRIIRKGIHIIKKY	Dental Caries	Phase 2 (completed 2017)	C16G2 Strip	NCT03052842	United States
		Dental Caries	Phase 2 (completed 2015, 2016 and 2018)	C16G2	NCT02254993, NCT02509845, NCT03196219	United States
		Dental Caries	Phase 2 (completed 2017)	C16G2 Varnish	NCT03004365	United States
		Dental Caries	Phase 2 (completed 2016)	C16G2 Gel	NCT02594254	United States
		Dental Caries	Phase 2 (completed 2014)	C16G2 Rinse and Gel	NCT02044081	United States
Iseganan (IB-367)	RGGLCYCRGRFCVCVGR	Pneumonia	Phase 3 (completed 2004)	Iseganan hydrochloride	NCT00118781	United States
PAC-113	Histatin 5 derivative	Oral Candidiasis	Phase 2 (completed 2008)	PAC113 mouthrinse	NCT00659971	United States
Murepavadin (POL7080)	LSYXXxXWXXASpP	Bronchiectasis Lower Respiratory Infection	Phase 2 (completed 2015)	POL7080	NCT02096315	United Kingdom
		Ventilator Associated Pneumonia, Lower Respiratory Infection	Phase 2 (completed 2016)	POL7080	NCT02096328	Greece
PXL01	Derived from human lactoferricin	Surgical Adhesions	Phase 2 (completed 2013)	PXL01	NCT01022242	Denmark
Dusquetide (SGX942)	RIVPA	Oral Mucositis	Phase 3 (completed 2021)	SGX942	NCT03237325	United States
		Oral Mucositis	Phase 2 (completed 2016)	SGX942	NCT02013050	United States

Figure 3 Different cellular uptake mechanisms of CPPs. (A) Direct translocation models including (a) the barrel-stave model; (b) the toroidal model; (c) inverted micelle formation; and (d) the carpet model.⁸² (B) Pinocytosis models including (a) macropinocytosis; (b) clathrin-mediated endocytosis; (c) caveolin-mediated endocytosis; and (d) clathrin/caveolin-independent endocytosis. The short green curves represent CPPs.

Notes: Adapted from Szabó I, Yousef M, Soltész D, Bató C, Mező G, Bánóczi Z. Redesigning of cell-penetrating peptides to improve their efficacy as a drug delivery system. Pharmaceutics. 2022;14(5):907. Copyright © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/.⁸²

Pirtskhalava M, Amstrong AA, Grigolava M, et al. DBAASP v3: database of antimicrobial/cytotoxic activity and structure of peptides as a resource for development of new therapeutics. Nucleic Acids Res. 2021;49(D1):D288–D297.

 PubMed Web of Science ®Google Scholar

Huan Y, Kong Q, Mou H, Yi H. Antimicrobial peptides: classification, design, application and research progress in multiple fields. Front Microbiol. 2020;11:582779.

 PubMed Web of Science ®Google Scholar

Szabó I, Yousef M, Soltész D, Bató C, Mező G, Bánóczi Z. Redesigning of cell-penetrating peptides to improve their efficacy as a drug delivery system. Pharmaceutics. 2022;14(5):907.

 PubMed Web of Science ®Google Scholar