Activity of Human Defensins HNP-1 and HBD-3 Against Multidrug-resistant ESKAPE Gram-negatives of Clinical Origin and Selected Peptidoglycan Recycling-defective Mutants

Overview

Journal Microbiol Spectr

Specialty Microbiology

Date 2024 Mar 5

PMID 38441982

Authors

Maria Escobar-Salom

Isabel Maria Barcelo

Estrella Rojo-Molinero

Elena Jordana-Lluch

Gabriel Cabot

Antonio Oliver

Carlos Juan

Affiliations

Soon will be listed here.

Abstract

Importance: In the current scenario of critical need for new antimicrobials against multidrug-resistant bacteria, all options must be considered, including classic ideas such as the use of purified immune compounds. However, information regarding the activity of certain human defensins against ESKAPE Gram-negatives was incomplete. This is the first study comparatively assessing the in vitro activity of two membrane-permeabilizing/peptidoglycan construction-blocking defensins (HNP-1 and hBD-3) against relevant clinical collections of ESKAPE Gram-negatives, alone or in combination with permeabilizers, additional peptidoglycan-targeting attacks, or the blockade of its recycling. Our data suggest that hBD-3 has a notable bactericidal activity against multidrug-resistant and strains that should be considered as potential adjuvant option. Our results suggest for the first time an increased resistance of strains from chronic infection compared to acute origin ones, and provide new clues about the predominant mode of action of hBD-3 against Gram-negatives (permeabilization rather than peptidoglycan-targeting).

References

Wiegand I, Hilpert K, Hancock R . Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc. 2008; 3(2):163-75. DOI: 10.1038/nprot.2007.521. View

Scudiero O, Galdiero S, Nigro E, Del Vecchio L, Di Noto R, Cantisani M . Chimeric beta-defensin analogs, including the novel 3NI analog, display salt-resistant antimicrobial activity and lack toxicity in human epithelial cell lines. Antimicrob Agents Chemother. 2013; 57(4):1701-8. PMC: 3623310. DOI: 10.1128/AAC.00934-12. View

Nigro E, Colavita I, Sarnataro D, Scudiero O, Zambrano G, Granata V . An ancestral host defence peptide within human β-defensin 3 recapitulates the antibacterial and antiviral activity of the full-length molecule. Sci Rep. 2015; 5:18450. PMC: 4685272. DOI: 10.1038/srep18450. View

He J, Starr C, Wimley W . A lack of synergy between membrane-permeabilizing cationic antimicrobial peptides and conventional antibiotics. Biochim Biophys Acta. 2014; 1848(1 Pt A):8-15. PMC: 4259837. DOI: 10.1016/j.bbamem.2014.09.010. View

Lennard P, Hiemstra P, Nibbering P . Complementary Activities of Host Defence Peptides and Antibiotics in Combating Antimicrobial Resistant Bacteria. Antibiotics (Basel). 2023; 12(10). PMC: 10604037. DOI: 10.3390/antibiotics12101518. View

Paone G, Stevens L, Levine R, Bourgeois C, Steagall W, Gochuico B . ADP-ribosyltransferase-specific modification of human neutrophil peptide-1. J Biol Chem. 2006; 281(25):17054-17060. DOI: 10.1074/jbc.M603042200. View

Malin J, de Leeuw E . Therapeutic compounds targeting Lipid II for antibacterial purposes. Infect Drug Resist. 2019; 12:2613-2625. PMC: 6711568. DOI: 10.2147/IDR.S215070. View

Sadek M, Le Guern R, Kipnis E, Gosset P, Poirel L, Dessein R . Progressive in vivo development of resistance to cefiderocol in Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis. 2022; 42(1):61-66. PMC: 9816264. DOI: 10.1007/s10096-022-04526-0. View

Wilmes M, Cammue B, Sahl H, Thevissen K . Antibiotic activities of host defense peptides: more to it than lipid bilayer perturbation. Nat Prod Rep. 2011; 28(8):1350-8. DOI: 10.1039/c1np00022e. View

10.

Escobar-Salom M, Torrens G, Jordana-Lluch E, Oliver A, Juan C . Mammals' humoral immune proteins and peptides targeting the bacterial envelope: from natural protection to therapeutic applications against multidrug-resistant Gram-negatives. Biol Rev Camb Philos Soc. 2022; 97(3):1005-1037. PMC: 9304279. DOI: 10.1111/brv.12830. View

11.

Barcelo I, Torrens G, Escobar-Salom M, Jordana-Lluch E, Capo-Bauza M, Ramon-Pallin C . Impact of Peptidoglycan Recycling Blockade and Expression of Horizontally Acquired β-Lactamases on Pseudomonas aeruginosa Virulence. Microbiol Spectr. 2022; 10(1):e0201921. PMC: 8849096. DOI: 10.1128/spectrum.02019-21. View

12.

Gela A, Bhongir R, Mori M, Keenan P, Morgelin M, Erjefalt J . Osteopontin That Is Elevated in the Airways during COPD Impairs the Antibacterial Activity of Common Innate Antibiotics. PLoS One. 2016; 11(1):e0146192. PMC: 4712133. DOI: 10.1371/journal.pone.0146192. View

13.

Nuding S, Frasch T, Schaller M, Stange E, Zabel L . Synergistic effects of antimicrobial peptides and antibiotics against Clostridium difficile. Antimicrob Agents Chemother. 2014; 58(10):5719-25. PMC: 4187972. DOI: 10.1128/AAC.02542-14. View

14.

Porro G, Lee J, de Azavedo J, Crandall I, Whitehead T, Tullis E . Direct and indirect bacterial killing functions of neutrophil defensins in lung explants. Am J Physiol Lung Cell Mol Physiol. 2001; 281(5):L1240-7. DOI: 10.1152/ajplung.2001.281.5.L1240. View

15.

Faure E, Kwong K, Nguyen D . in Chronic Lung Infections: How to Adapt Within the Host?. Front Immunol. 2018; 9:2416. PMC: 6204374. DOI: 10.3389/fimmu.2018.02416. View

16.

Barcelo I, Escobar-Salom M, Jordana-Lluch E, Torrens G, Oliver A, Juan C . Filling knowledge gaps related to AmpC-dependent β-lactam resistance in Enterobacter cloacae. Sci Rep. 2024; 14(1):189. PMC: 10762043. DOI: 10.1038/s41598-023-50685-1. View

17.

Torrens G, Barcelo I, Perez-Gallego M, Escobar-Salom M, Tur-Gracia S, Munar-Bestard M . Publisher Correction: Profiling the susceptibility of Pseudomonas aeruginosa strains from acute and chronic infections to cell-wall-targeting immune proteins. Sci Rep. 2020; 10(1):4356. PMC: 7055294. DOI: 10.1038/s41598-020-60494-5. View

18.

Sahly H, Schubert S, Harder J, Kleine M, Sandvang D, Ullmann U . Activity of human beta-defensins 2 and 3 against ESBL-producing Klebsiella strains. J Antimicrob Chemother. 2006; 57(3):562-5. DOI: 10.1093/jac/dkl003. View

19.

Li T, Guo F, Wang Q, Fang H, Li Z, Wang D . N-terminus three residues deletion mutant of human beta-defensin 3 with remarkably enhanced salt-resistance. PLoS One. 2015; 10(2):e0117913. PMC: 4338079. DOI: 10.1371/journal.pone.0117913. View

20.

Campos M, Vargas M, Regueiro V, Llompart C, Alberti S, Bengoechea J . Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect Immun. 2004; 72(12):7107-14. PMC: 529140. DOI: 10.1128/IAI.72.12.7107-7114.2004. View