Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Development and Evaluation of the Efficacy and Toxicity of a New Hybrid Antimicrobial Peptide MY8

Author(s): Nasr Alrabadi*, Maryam Hamdan, Razan Haddad, Salsabeel H. Sabi, Majed M. Masadeh, Karem H. Alzoubi and Khalid M. Al-Batayneh

Volume 29, Issue 43, 2023

Published on: 11 December, 2023

Page: [3488 - 3496] Pages: 9

DOI: 10.2174/0113816128277632231201043542

Price: $65

conference banner
Abstract

Background: Antibiotics have led to significant advancements in medicine. Unfortunately, they were faced with the emergence of pathogen resistance. According to the World Health Organization, antimicrobial resistance has been declared one of humanity's top ten global public health threats. The risk of those bacteria is not only from their being resistant to multi-antibiotics but also from their ability to form biofilms, which can be 1,000 times more resistant than planktonic bacteria.

Method: This study used rational design to hybridize two antimicrobial peptides, aiming to enhance their efficacy and stability with reduced toxicity.

Results: The MY8 novel peptide was designed from the parent peptides BMAP-27 and CAMP 211-225. Some amino acid modifications were introduced to the hybrid peptide to improve its physicochemical properties guided by several software. Its antimicrobial activity has been studied against gram-negative and gram-positive strains, which showed broad-spectrum activity with MIC values against planktonic bacteria ranging from 0.125 to 25 μM. In contrast, 25-200 μM were needed to eradicate biofilms. Moreover, the MY8 peptide showed synergism with four conventional antibiotics., It also showed reduced toxicity against mammalian cells and a slight hemolysis tendency towards erythrocytes.

Conclusion: The design of the MY8 peptide was successful, resulting in a novel, potent, broad-spectrum antimicrobial peptide with reduced toxicity and possible synergism with conventional antibiotics.

Keywords: Antimicrobial peptides, antimicrobial resistance, anti-biofilm, synergism, antibiotics, resistance.

« Previous Next »
[1]
Aslam B, Wang W, Arshad MI, et al. Antibiotic resistance: A rundown of a global crisis. Infect Drug Resist 2018; 11: 1645-58.
[http://dx.doi.org/10.2147/IDR.S173867] [PMID: 30349322]
[2]
Gajdács M, Albericio F. Antibiotic resistance: From the bench to patients. Antibiotics 2019; 8(3): 129.
[http://dx.doi.org/10.3390/antibiotics8030129] [PMID: 31461842]
[3]
Guo Y, Song G, Sun M, Wang J, Wang Y. Prevalence and therapies of antibiotic-resistance in Staphylococcus aureus. Front Cell Infect Microbiol 2020; 10: 107.
[http://dx.doi.org/10.3389/fcimb.2020.00107] [PMID: 32257966]
[4]
Mobarki N, Almerabi B, Hattan A. Antibiotic resistance crisis. Int J Med Dev Ctries 2019; 40: 561-4.
[5]
Almaaytah A, Alnaamneh A, Abualhaijaa A, Alshari’ N, Al-Balas Q. In vitro synergistic activities of the hybrid antimicrobial peptide MelitAP-27 in combination with conventional antibiotics against planktonic and biofilm forming bacteria. Int J Pept Res Ther 2016; 22(4): 497-504.
[http://dx.doi.org/10.1007/s10989-016-9530-z]
[6]
Wang S, Zhao S, Zhou Y, Jin S, Ye T, Pan X. Antibiotic resistance spectrum of E. coli strains from different samples and age-grouped patients: A 10-year retrospective study. BMJ Open 2023; 13(4): e067490.
[http://dx.doi.org/10.1136/bmjopen-2022-067490] [PMID: 37045577]
[7]
Frieri M, Kumar K, Boutin A. Antibiotic resistance. J Infect Public Health 2017; 10(4): 369-78.
[http://dx.doi.org/10.1016/j.jiph.2016.08.007] [PMID: 27616769]
[8]
Almaaytah A, Qaoud MT, Abualhaijaa A, Al-Balas Q, Alzoubi KH. Hybridization and antibiotic synergism as a tool for reducing the cytotoxicity of antimicrobial peptides. Infect Drug Resist 2018; 11: 835-47.
[http://dx.doi.org/10.2147/IDR.S166236] [PMID: 29910626]
[9]
Almaaytah A, Mohammed G, Abualhaijaa A, Al-Balas Q. Development of novel ultrashort antimicrobial peptide nanoparticles with potent antimicrobial and antibiofilm activities against multidrug-resistant bacteria. Drug Des Devel Ther 2017; 11: 3159-70.
[http://dx.doi.org/10.2147/DDDT.S147450] [PMID: 29138537]
[10]
Almaaytah A, Ajingi Y, Abualhaijaa A, Tarazi S, Alshar’i N, Al-Balas Q. Peptide consensus sequence determination for the enhancement of the antimicrobial activity and selectivity of antimicrobial peptides. Infect Drug Resist 2016; 10: 1-17.
[http://dx.doi.org/10.2147/IDR.S118877] [PMID: 28096686]
[11]
Kim JY, Park SC, Hwang I, et al. Protease inhibitors from plants with antimicrobial activity. Int J Mol Sci 2009; 10(6): 2860-72.
[http://dx.doi.org/10.3390/ijms10062860] [PMID: 19582234]
[12]
Kościuczuk EM, Lisowski P, Jarczak J, et al. Cathelicidins: Family of antimicrobial peptides. A review. Mol Biol Rep 2012; 39(12): 10957-70.
[http://dx.doi.org/10.1007/s11033-012-1997-x] [PMID: 23065264]
[13]
Zanetti M. The role of Cathelicidins in the innate immune response. 1995; 179-96.
[14]
Benincasa M, Scocchi M, Pacor S, et al. Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts. J Antimicrob Chemother 2006; 58(5): 950-9.
[http://dx.doi.org/10.1093/jac/dkl382] [PMID: 17023499]
[15]
Benincasa M, Skerlavaj B, Gennaro R, Pellegrini A, Zanetti M. In vitro and in vivo antimicrobial activity of two α-helical cathelicidin peptides and of their synthetic analogs. Peptides 2003; 24(11): 1723-31.
[http://dx.doi.org/10.1016/j.peptides.2003.07.025] [PMID: 15019203]
[16]
Mardirossian M, Pompilio A, Crocetta V, et al. In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections. Amino Acids 2016; 48(9): 2253-60.
[http://dx.doi.org/10.1007/s00726-016-2266-4] [PMID: 27270571]
[17]
Pompilio A, Crocetta V, Scocchi M, et al. Potential novel therapeutic strategies in cystic fibrosis: Antimicrobial and anti-biofilm activity of natural and designed α-helical peptides against Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. BMC Microbiol 2012; 12(1): 145.
[http://dx.doi.org/10.1186/1471-2180-12-145] [PMID: 22823964]
[18]
Skerlavaj B, Gennaro R, Bagella L, Merluzzi L, Risso A, Zanetti M. Biological characterization of two novel cathelicidin-derived peptides and identification of structural requirements for their antimicrobial and cell lytic activities. J Biol Chem 1996; 271(45): 28375-81.
[http://dx.doi.org/10.1074/jbc.271.45.28375] [PMID: 8910461]
[19]
Ahmad A, Azmi S, Srivastava RM, et al. Design of nontoxic analogues of cathelicidin-derived bovine antimicrobial peptide BMAP-27: The role of leucine as well as phenylalanine zipper sequences in determining its toxicity. Biochemistry 2009; 48(46): 10905-17.
[http://dx.doi.org/10.1021/bi9009874] [PMID: 19845398]
[20]
Yang S, Lee CW, Kim HJ, et al. Structural analysis and mode of action of BMAP-27, a cathelicidin-derived antimicrobial peptide. Peptides 2019; 118: 170106.
[http://dx.doi.org/10.1016/j.peptides.2019.170106] [PMID: 31226350]
[21]
Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002; 415(6870): 389-95.
[http://dx.doi.org/10.1038/415389a] [PMID: 11807545]
[22]
Rotem S, Mor A, Otero-Gonzáiez AJ, et al. NIH public access. Infect Drug Resist 2017; 11: 1-7.
[23]
Cui X, Li Y, Yang L, et al. Peptidome analysis of human milk from women delivering macrosomic fetuses reveals multiple means of protection for infants. Oncotarget 2016; 7(39): 63514-25.
[http://dx.doi.org/10.18632/oncotarget.11532] [PMID: 27566575]
[24]
Xiao H, Jiang H, Tu H, et al. Extraction, isolation and identification of low molecular weight peptides in human milk. Foods 2022; 11(13): 1836.
[http://dx.doi.org/10.3390/foods11131836] [PMID: 35804652]
[25]
Bhatia J. Human milk for preterm infants and fortification. Nestle Nutr Inst Workshop Ser 2016; 86: 109-19.
[http://dx.doi.org/10.1159/000442730] [PMID: 27347886]
[26]
Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol 2009; 29(1): 57-62.
[http://dx.doi.org/10.1038/jp.2008.117] [PMID: 18716628]
[27]
Victora CG, Barros AJ, Fuchs SC, et al. Effect of breastfeeding on infant and child mortality due to infectious diseases in less developed countries: A pooled analysis. Lancet 2000; 355(9202): 451-5.
[http://dx.doi.org/10.1016/S0140-6736(00)82011-5] [PMID: 10841125]
[28]
Atamer Z, Post AE, Schubert T, Holder A, Boom RM, Hinrichs J. Bovine β-casein: Isolation, properties and functionality. A review. Int Dairy J 2017; 66: 115-25.
[http://dx.doi.org/10.1016/j.idairyj.2016.11.010]
[29]
Faizullin DA, Konnova TA, Haertlé T, Zuev YF. Secondary structure and colloidal stability of beta-casein in microheterogeneous water-ethanol solutions. Food Hydrocoll 2017; 63: 349-55.
[http://dx.doi.org/10.1016/j.foodhyd.2016.09.011]
[30]
Głąb TK, Boratyński J. Potential of casein as a carrier for biologically active agents. Top Curr Chem 2017; 375(4): 71.
[http://dx.doi.org/10.1007/s41061-017-0158-z] [PMID: 28712055]
[31]
Wang X, Sun Y, Wang F, et al. A novel endogenous antimicrobial peptide CAMP211-225 derived from casein in human milk. Food Funct 2020; 11(3): 2291-8.
[http://dx.doi.org/10.1039/C9FO02813G] [PMID: 32104859]
[32]
Combet C, Blanchet C GC. NPS@: Network protein sequence analysis. Trends Biochem Sci 2000; 25(3): 147-50.
[33]
Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RDB. Protein Identification and Analysis Tools on the Expasy Server. The Proteomics Protocols Handbook. Humana Press 2005; pp. 571-607.
[http://dx.doi.org/10.1385/1-59259-890-0:571]
[34]
Wang G, Li X, Wang Z. APD3: The antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 2016; 44(D1): D1087-93.
[http://dx.doi.org/10.1093/nar/gkv1278] [PMID: 26602694]
[35]
Gautier R, Douguet D, Antonny B, Drin G. HELIQUEST: A web server to screen sequences with specific α-helical properties. Bioinformatics 2008; 24(18): 2101-2.
[http://dx.doi.org/10.1093/bioinformatics/btn392] [PMID: 18662927]
[36]
Roy A, Kucukural A, Zhang Y. I-TASSER: A unified platform for automated protein structure and function prediction. Nat Protoc 2010; 5(4): 725-38.
[http://dx.doi.org/10.1038/nprot.2010.5] [PMID: 20360767]
[37]
Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER Suite: Protein structure and function prediction. Nat Methods 2015; 12(1): 7-8.
[http://dx.doi.org/10.1038/nmeth.3213] [PMID: 25549265]
[38]
Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinf 2008; 9(1): 40.
[http://dx.doi.org/10.1186/1471-2105-9-40] [PMID: 18215316]
[39]
Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: A review of general principles and contemporary practices. Clin Infect Dis 2009; 49(11): 1749-55.
[http://dx.doi.org/10.1086/647952] [PMID: 19857164]
[40]
Bonapace CR, Bosso JA, Friedrich LV, White RL. Comparison of methods of interpretation of checkerboard synergy testing. Diagn Microbiol Infect Dis 2002; 44(4): 363-6.
[http://dx.doi.org/10.1016/S0732-8893(02)00473-X] [PMID: 12543542]
[41]
Cokol-Cakmak M, Cokol M. Miniaturized checkerboard assays to measure antibiotic interactions. Methods Mol Biol 2019; 1939: 3-9.
[http://dx.doi.org/10.1007/978-1-4939-9089-4_1] [PMID: 30848453]
[42]
Hall MJ, Middleton RF, Westmacott D. The fractional inhibitory concentration (FIC) index as a measure of synergy. J Antimicrob Chemother 1983; 11(5): 427-33.
[http://dx.doi.org/10.1093/jac/11.5.427] [PMID: 6874629]
[43]
Botelho MG. Fractional inhibitory concentration index of combinations of antibacterial agents against cariogenic organisms. J Dent 2000; 28(8): 565-70.
[http://dx.doi.org/10.1016/S0300-5712(00)00039-7] [PMID: 11082524]
[44]
Meletiadis J, Pournaras S, Roilides E, Walsh TJ. Defining fractional inhibitory concentration index cutoffs for additive interactions based on self-drug additive combinations, Monte Carlo simulation analysis, and in vitro-in vivo correlation data for antifungal drug combinations against Aspergillus fumigatus. Antimicrob Agents Chemother 2010; 54(2): 602-9.
[http://dx.doi.org/10.1128/AAC.00999-09] [PMID: 19995928]
[45]
Haney EF, Trimble MJ, Hancock REW. Microtiter plate assays to assess antibiofilm activity against bacteria. Nat Protoc 2021; 16(5): 2615-32.
[http://dx.doi.org/10.1038/s41596-021-00515-3] [PMID: 33911258]
[46]
Parker AE, Walker DK, Goeres DM, Allan N, Olson ME, Omar A. Ruggedness and reproducibility of the MBEC biofilm disinfectant efficacy test. J Microbiol Methods 2014; 102: 55-64.
[http://dx.doi.org/10.1016/j.mimet.2014.04.013] [PMID: 24815513]
[47]
Bastos JC, Vieira NSM, Gaspar MM, Pereiro AB, Araújo JMM. Human cytotoxicity, hemolytic activity, anti-inflammatory activity and aqueous solubility of ibuprofen-based ionic liquids. Sustain Chem 2022; 3(3): 358-75.
[http://dx.doi.org/10.3390/suschem3030023]
[48]
Powers JPS, Hancock REW, Yoshida M, et al. A polyalanine peptide derived from polar fish with anti-infectious activities. Expert Rev Anti Infect Ther 2006; 5: 337-49.
[49]
Rowe GE, Welch RA. Assays of hemolytic toxins. Methods Enzymol 1994; 235: 657-67.
[http://dx.doi.org/10.1016/0076-6879(94)35179-1] [PMID: 7520121]
[50]
Marin V, Kaplanski G, Grès S, Farnarier C, Bongrand P. Endothelial cell culture: Protocol to obtain and cultivate human umbilical endothelial cells. J Immunol Methods 2001; 254(1-2): 183-90.
[http://dx.doi.org/10.1016/S0022-1759(01)00408-2] [PMID: 11406163]
[51]
Supino R. MTT assays. Methods Mol Biol 1995; 43: 137-49.
[PMID: 7550641]
[52]
van Meerloo J, Kaspers GJL, Cloos J. Cell sensitivity assays: The MTT assay. In: Cree IA, Ed. Cancer Cell Culture: Methods and Protocols. Totowa, NJ: Humana Press 2011; pp. 237-45.
[http://dx.doi.org/10.1007/978-1-61779-080-5_20]
[53]
Gilbert DN, Guidos RJ, Boucher HW, et al. The 10 x ’20 Initiative: Pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis 2010; 50(8): 1081-3.
[http://dx.doi.org/10.1086/652237] [PMID: 20214473]
[54]
Fjell CD, Hiss JA, Hancock REW, Schneider G. Designing antimicrobial peptides: Form follows function. Nat Rev Drug Discov 2012; 11(1): 37-51.
[http://dx.doi.org/10.1038/nrd3591] [PMID: 22173434]
[55]
De Souza Cândido E. The use of versatile plant antimicrobial peptides in agribusiness and human health. Peptides 2014; 55: 65-78.
[56]
Dorschner RA, Lopez-Garcia B, Peschel A, et al. The mammalian ionic environment dictates microbial susceptibility to antimicrobial defense peptides. FASEB J 2006; 20(1): 35-42.
[http://dx.doi.org/10.1096/fj.05-4406com] [PMID: 16394265]
[57]
Tossi A, Tarantino C, Romeo D. Design of synthetic antimicrobial peptides based on sequence analogy and amphipathicity. Eur J Biochem 1997; 250(2): 549-58.
[http://dx.doi.org/10.1111/j.1432-1033.1997.0549a.x] [PMID: 9428709]
[58]
Wade HM, Darling LEO, Elmore DE. Hybrids made from antimicrobial peptides with different mechanisms of action show enhanced membrane permeabilization. Biochim Biophys Acta Biomembr 2019; 1861(10): 182980.
[http://dx.doi.org/10.1016/j.bbamem.2019.05.002] [PMID: 31067436]
[59]
Chen N, Jiang C. Antimicrobial peptides: Structure, mechanism, and modification. Eur J Med Chem 2023; 255: 115377.
[http://dx.doi.org/10.1016/j.ejmech.2023.115377] [PMID: 37099837]
[60]
Lima PG, Oliveira JTA, Amaral JL, Freitas CDT, Souza PFN. Synthetic antimicrobial peptides: Characteristics, design, and potential as alternative molecules to overcome microbial resistance. Life Sci 2021; 278: 119647.
[http://dx.doi.org/10.1016/j.lfs.2021.119647] [PMID: 34043990]
[61]
Huang Y, He L, Li G, Zhai N, Jiang H, Chen Y. Role of helicity of α-helical antimicrobial peptides to improve specificity. Protein Cell 2014; 5(8): 631-42.
[http://dx.doi.org/10.1007/s13238-014-0061-0] [PMID: 24805306]
[62]
Chen Y, Guarnieri MT, Vasil AI, Vasil ML, Mant CT, Hodges RS. Role of peptide hydrophobicity in the mechanism of action of α-helical antimicrobial peptides. Antimicrob Agents Chemother 2007; 51(4): 1398-406.
[http://dx.doi.org/10.1128/AAC.00925-06] [PMID: 17158938]
[63]
Mahlapuu M, Håkansson J, Ringstad L, Björn C. Antimicrobial peptides: An emerging category of therapeutic agents. Front Cell Infect Microbiol 2016; 6: 194.
[http://dx.doi.org/10.3389/fcimb.2016.00194] [PMID: 28083516]
[64]
Yan H, Hancock REW. Synergistic interactions between mammalian antimicrobial defense peptides. Antimicrob Agents Chemother 2001; 45(5): 1558-60.
[http://dx.doi.org/10.1128/AAC.45.5.1558-1560.2001] [PMID: 11302828]
[65]
Scott MG, Yan H, Hancock REW. Biological properties of structurally related α-helical cationic antimicrobial peptides. Infect Immun 1999; 67(4): 2005-9.
[http://dx.doi.org/10.1128/IAI.67.4.2005-2009.1999] [PMID: 10085049]
[66]
Weber M, Steinle H, Golombek S, et al. Blood-contacting biomaterials: In vitro evaluation of the hemocompatibility. Front Bioeng Biotechnol 2018; 6: 99.
[http://dx.doi.org/10.3389/fbioe.2018.00099]

Rights & Permissions Print Cite
Article Metrics
35
2
Wayfinder Image
World Antimicrobial Awareness Week
© 2024 Bentham Science Publishers | Privacy Policy