Anti-adhesion Properties of 4-(adamantyl-1)-1-(1-aminobutyl)benzole Against Staphylococcus aureus

Authors

DOI:

https://doi.org/10.20535/ibb.2025.9.2.313507

Keywords:

adamantane derivative, Staphylococcus aureus, gene expression, biofilm, adhesion

Abstract

Background. Staphylococcus aureus is classified as a bacterium with a high level of antibiotic resistance, one of the contributing factors being its ability to form biofilms. Targeting the early stages of biofilm formation is a promising strategy for antimicrobial therapy in patients with biofilm-associated infections.

Objective. To determine the ability of 4-(adamantyl-1)-1-(1-aminobutyl)benzole to influence the formation of S. aureus biofilms and the expression of biofilm formation genes.

Methods. The minimum inhibitory concentration (MIC) of 4-(adamantyl-1)-1-(1-aminobutyl)benzole (code AM-166) against the methicillin-resistant S. aureus strain 222 was determined using the serial microdilution method. The antibiofilm activity of AM-166 was studied using O'Toole's method, and the intensity of S. aureus biofilm formation was assessed according to Stepanovic. The effect of AM-166 on gene expression was investigated using real-time PCR.

Results. The MIC of AM-166 against S. aureus 222 was determined to be 5 μg/ml. In the presence of AM-166 at 0.25 and 0.5 MIC, S. aureus biofilm formation decreased from moderate (control) to weak, while at 5.0 MIC, the strain completely lost its ability to form biofilms. It was found that at a concentration of 0.5 MIC, AM-166 increased the expression of the icaR gene while decreasing the transcriptional activity of the icaA, clfB, fib, fnbB, ebpS, and eno genes, which are involved in biofilm formation and adhesion.

Conclusions. The adamantane derivative AM-166 disrupts MRSA biofilm formation, alters the transcriptional activity of ica-locus genes, and inhibits S. aureus attachment to biotic surfaces by affecting gene expression.

References

European Comission. A European one health action plan against antimicrobial resistance (AMR) [Internet]. health.ec.europa.eu. 2024 [cited 2024 Oct 10]. Available from: https://ec.europa.eu/health/system/files/2020-01/amr_2017_action-plan_0.pdf

Widmer AF. Emerging antibiotic resistance: Why we need new antibiotics! Swiss Med Wkly. 2022 Nov 9;152:40032. DOI: 10.57187/smw.2022.40032

Tang KWK, Millar BC, Moore JE. Antimicrobial Resistance (AMR). Br J Biomed Sci. 2023 Jun 28;80:11387. DOI: 10.3389/bjbs.2023.11387

Idrees M, Sawant S, Karodia N, Rahman A. Staphylococcus aureus biofilm: morphology, genetics, pathogenesis and treatment strategies. Int J Environ Res Public Health. 2021 Jul 16;18(14):7602. DOI: 10.3390/ijerph18147602

Shin HJ, Yang S, Lim Y. Antibiotic susceptibility of Staphylococcus aureus with different degrees of biofilm formation. J Anal Sci Technol. 2021;12:41. DOI: 10.1186/s40543-021-00294-2

World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed [Internet]. World Health Organization. 2017 [cited 2024 Oct 10]. Available from: https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed

Mancuso G, Midiri A, Gerace E, Biondo C. Bacterial antibiotic resistance: The most critical pathogens. Pathogens. 2021 Oct 12;10(10):1310. DOI: 10.3390/pathogens10101310

John J Jr. The treatment of resistant staphylococcal infections. F1000Res. 2020 Feb 26;9:F1000 Faculty Rev-150. DOI: 10.12688/f1000research.17718.1

Tuon FF, Suss PH, Telles JP, Dantas LR, Borges NH, Ribeiro VST. Antimicrobial treatment of Staphylococcus aureus biofilms. Antibiotics. 2023;12(1):87. DOI: 10.3390/antibiotics12010087

Kranjec C, Morales Angeles D, Torrissen Mårli M, Fernández L, García P, Kjos M, et al. Staphylococcal biofilms: Chal-lenges and novel therapeutic perspectives. Antibiotics (Basel). 2021 Jan 29;10(2):131. DOI: 10.3390/antibiotics10020131

Schilcher K, Horswill AR. Staphylococcal biofilm development: Structure, regulation, and treatment strategies. Microbiol Mol Biol Rev. 2020 Aug 12;84(3):e00026-19. DOI: 10.1128/MMBR.00026-19

Foster TJ. Surface proteins of Staphylococcus aureus. Microbiol Spectr. 2019; 7(4). DOI: 10.1128/microbiolspec.GPP3-0046-2018

Nguyen HTT, Nguyen TH, Otto M. The staphylococcal exopolysaccharide PIA - Biosynthesis and role in biofilm formation, colonization, and infection. Comput Struct Biotechnol J. 2020 Nov 4;18:3324-34. DOI: 10.1016/j.csbj.2020.10.027

Al-Wahaibi LH, Hassan HM, Abo-Kamar AM, Ghabbour HA, El-Emam AA. Adamantane-Isothiourea hybrid derivatives: Synthesis, characterization, in vitro antimicrobial, and in vivo hypoglycemic activities. Molecules. 2017 Apr 29;22(5):710. DOI: 10.3390/molecules22050710

Zhan W, Gao G, Liu Z, Liu X, Xu L, Wang M, et al. Enzymatic self-assembly of adamantane-peptide conjugate for combating Staphylococcus aureus infection. Adv Healthc Mater. 2023 Jul;12(18):e2203283. DOI: 10.1002/adhm.202203283

Tan F, She P, Zhou L, Liu Y, Chen L, Luo Z, et al. Bactericidal and anti-biofilm activity of the retinoid compound CD437 against Enterococcus faecalis. Front Microbiol. 2019;10:2301. DOI: 10.3389/fmicb.2019.02301

Humeniuk N, Zelena L, Vrynchanu N, Ishchenko L, Bukhtiarova T, Korotkij Y, et al. Effect of adamantane derivative on expression of biofilm-associated genes in methicillin-resistant Staphylococcus aureus. Med Drug Discov. 2023;18:100155. DOI: 10.1016/j.medidd.2023.100155

ISO 20776-1:2019. Susceptibility testing of infectious agents and evaluation of performance of antimicrobial susceptibility test devices Part 1: Broth micro-dilution reference method for testing the in vitro activity of antimicrobial agents against rapidly growing aerobic bacteria involved in infectious diseases. Geneva: International Organization for Standardization. 2019. Available at: https://www.iso.org/standard/70464.html

O'Toole GA. Microtiter dish biofilm formation assay. J Vis Exp. 2011 Jan 30;(47):2437. DOI: 10.3791/2437

Stepanović S, Vuković D, Hola V, Di Bonaventura G, Djukić S, Cirković I, et al. Quantification of biofilm in microtiter plates: overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci. APMIS. 2007 Aug;115(8):891-9. DOI: 10.1111/j.1600-0463.2007.apm_630.x

Atshan SS, Nor Shamsudin M, Sekawi Z, Lung LT, Hamat RA, Karunanidhi A, et al. Prevalence of adhesion and regulation of biofilm-related genes in different clones of Staphylococcus aureus. J Biomed Biotechnol. 2012;2012:976972. DOI: 10.1155/2012/976972

Melo TA, Dos Santos TF, de Almeida ME, Junior LAGF, Andrade EF, Rezende RP, et al. Inhibition of Staphylococcus aureus biofilm by Lactobacillus isolated from fine cocoa. BMC Microbiol 2016;16(1):250. DOI: 10.1186/s12866-016-0871-8

Zelena L, Gretsky I, Gromozova E. Influence of ultrahigh frequency irradiation on Photobacterium phosphoreum luxb gene expression. Cent Eur J Biol 2014;9:1004-10. DOI: 10.2478/s11535-014-0347-5

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001 Dec;25(4):402-8. DOI: 10.1006/meth.2001.1262

Wang L, Liu L, Zhang C, Yu G, Lin W, Duan X, et al. Design, synthesis, anti-infective potency and mechanism study of novel Ru-based complexes containing substituted adamantane as antibacterial agents. Eur J Med Chem. 2024 Apr 15;270:116378. DOI: 10.1016/j.ejmech.2024.116378

Hrynchuk N, Zelena L, Bukhtiarova T, Vrynchanu N, Ishchenko L, Vazhnichaya E. Antibiofilm activity of 4-(adamantyl-1)-1-(1-aminobutyl)benzol against methicillin-resistant Staphylococcus aureus. Mikrobiol Z. 2022;84(3):39-50. DOI: 10.15407/microbiolj84.03.039

Yu L, Hisatsune J, Kutsuno S, Sugai M. New molecular mechanism of superbiofilm elaboration in a Staphylococcus aureus clinical strain. Microbiol Spectr. 2023 Jan 31;11(2):e0442522. DOI: 10.1128/spectrum.04425-22

Fang ZY, Zhang ZY, Zheng YD, Lei D, Zhuang J, Li N, et al. Repurposing cinacalcet suppresses multidrug-resistant Staphylococcus aureus by disruption of cell membrane and inhibits biofilm by targeting IcaR. J Antimicrob Chemother. 2024 Apr 2;79(4):903-17. DOI: 10.1093/jac/dkae051

Mohammad GJ. Expression of icaA, B, D, R and ebps biofilm-associated genes in methicillin-resistant-Staphylococcus aureus in exposure to curcumin. Gene Rep. 2022;27:101616. DOI: 10.1016/j.genrep.2022.101616

Kuang H, Bi H, Li X, Lv X, Liu Y. Inhibition of S. aureus biofilm formation by linezolid alleviates sepsis-induced lung injury caused by S. aureus infection through direct inhibition of icaA activity. New Microbiol. 2023 Sep;46(3):285-95

Kot B, Sytykiewicz H, Sprawka I, Witeska M. Effect of manuka honey on biofilm associated genes expression during methicillin-resistant Staphylococcus aureus biofilm formation. Sci Rep. 2020;10(1):13552. DOI: 10.1038/s41598-020-70666-y

Qian Y, Xia L, Wei L, Li D, Jiang W. Artesunate inhibits Staphylococcus aureus biofilm formation by reducing alpha-toxin synthesis. Arch Microbiol. 2021 Mar; 203(2):707-17. DOI: 10.1007/s00203-020-02077-6

Atshan SS, Hamat RA, Coolen MJL, Dykes G, Sekawi Z, Mullins BJ, et al. The role of subinhibitory concentrations of daptomycin and tigecycline in modulating virulence in Staphylococcus aureus. Antibiotics (Basel). 2021 Jan 3;10(1):39. DOI: 10.3390/antibiotics10010039

Nasser A, Dallal MMS, Jahanbakhshi S, Azimi T, Nikouei L. Staphylococcus aureus: Biofilm formation and strategies against it. Curr Pharm Biotechnol. 2022;23(5):664-78. DOI: 10.2174/1389201022666210708171123

Published

2025-04-21

How to Cite

1.
Humeniuk N. Anti-adhesion Properties of 4-(adamantyl-1)-1-(1-aminobutyl)benzole Against Staphylococcus aureus. Innov Biosyst Bioeng [Internet]. 2025Apr.21 [cited 2025Apr.24];9(2):21-8. Available from: https://ibb.kpi.ua/article/view/313507